Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute

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Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute

Paths of
                                             Research and Care
                                             at Dana-Farber
                                             Cancer Institute

Cancer Cells With

Exploring the Human Microbiome
Making Progress Against Graft-Versus-Host Disease
Dana-Farber’s 2021 Annual Report
Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute

2022                                  Volume 29, Number 1


 8                                                                        20
FEATURES                                                         DEPARTMENTS
8 Targeting Cancer With Radiopharmaceuticals                      2 Around the Institute
These targeted radioactive drugs combine the power                News and highlights from Dana-Farber.
of pinpoint accuracy with the benefits of conventional
                                                                  30 Patient Focus
radiation therapy.
                                                                  Inspiring stories from our Insight blog.
14 Gut Instincts: Exploring the Human Microbiome
                                                                  31 Why I Work Here
The intestinal microbiome is one of the most diverse
                                                                  Brief conversations with staff across the Institute.
collections of microorganisms on the planet. Does it
hold any clues to cancer?                                         35 Dana-Farber 2021 Annual Report
20 The Enduring Legacy of David Livingston, MD
A titan among the giants of cancer research,
David Livingston, MD, left a legacy of groundbreaking
insights into cancer when he died unexpectedly in
late 2021.
26 Making Progress: Graft-Versus-Host Disease
Dana-Farber scientists help lead the worldwide
effort to end the most common side effect of
stem-cell transplant.

                           Vi si t Da n a - Fa r b e r o n lin e . www.d a n a -f a rb e r. o rg

                               Paths of Progress is published by Dana-Farber Cancer Institute.
                              Copyright © 2022 Dana-Farber Cancer Institute. All rights reserved.
Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute

   Dana-Farber Cancer Institute was founded by a man at odds
with the medical orthodoxy of his time, which held that there were
limitations on what cancer medicine could accomplish. Seventy-five
years later, that dissatisfaction with the status quo remains part of
the organization’s genome.
   In Dr. Sidney Farber’s era, the prevailing wisdom was that drugs
capable of killing cancer cells would be too toxic – too harmful – to
be useful. Farber’s success in using chemotherapy to produce the
first remissions of leukemia in children showed those concerns to
be unfounded (although it took the medical establishment several
years to fully embrace this approach).
   Farber summarized his philosophy this way: “I have never
accepted the incurability of cancer. And I have remained hopeful,
not because of wishful thinking – that’s not progress – but because
of the factual evidence of progress.” It’s hard to overstate how
radical that statement was for its era, a time when pediatric
leukemia was nearly always fatal, when survival periods for most
cancers were a fraction of what they are today, when many hospi-          “As we mark the Institute’s
tals didn’t have cancer wards because there was so little that could       75th anniversary this year, we
be done for patients.
                                                                           are the heirs not only of decades
   As we mark the Institute’s 75th anniversary this year, we are the
heirs not only of decades of advances against cancer but also of a         of advances against cancer but
way of thinking about cancer – not as a disease to be endured but          also of a way of thinking about
one to be defied and eventually defeated. Farber’s legacy to this
institution is the confidence that this mission can be accomplished.
                                                                           cancer – not as a disease to be
   Throughout our history, we’ve been fortunate to have others –           endured but one to be defied
donors, volunteers, supporters, community partners, patients, and          and eventually defeated.“
their families – who have shared our belief in the transformative
power of scientific inquiry and compassionate care. The story of
                                                                           – Laurie H. Glimcher, MD
the Institute is theirs as much as it is ours. The articles in Paths of
Progress are one way of presenting our work to those who may
benefit from it and those who have helped make it possible.
   Seventy-five years on, the scientific and humanistic qualities that
guided the Institute’s founding are alive and well.

Laurie H. Glimcher, MD
President and CEO, Dana-Farber Cancer Institute
Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute

$40 Million Transformative Grant Furthers Multiple Myeloma Research
                                                          – has led us to seek out the individuals, teams, and
                                                          organizations that are on the leading edge of re-
                                                          search,” said Rodger Riney. “There is no time to waste
                                                          in the pursuit of better understanding, treatment, and
                                                          cures. We hope this gift will inspire others to also
                                                          support the tremendous work happening every day in
                                                          Dana-Farber’s labs and clinics.”
                                                             The $40 million grant builds upon ongoing work and
                                                          will deepen and expand approaches for addressing
                                                          the most complex challenges in myeloma research
                                                          and improving patient care. Specifically, the grant will:
                                                            • Renew support for preclinical experiments to
                                                              identify novel targets and develop new medicines
                                                              and immune-based therapies for patients;
                                                            • Fund clinical research designed to test novel
                                                              myeloma therapies, alone and in combination with
                                                              standard and experimental treatments, to improve
Annamaria Gulla, MD (right), and Megan Johnstone in the       patient outcomes; and,
Multiple Myeloma lab.
                                                            • Support the co-location of myeloma labs at
   In early 2022, Paula and Rodger Riney of St. Louis,
                                                              Dana-Farber to facilitate greater cohesion
Mo, through the Paula and Rodger Riney Foundation,
                                                              and collaboration among members of the
announced a $40 million grant to support multiple
                                                              research team.
myeloma research at Dana-Farber, representing the
largest single award supporting multiple myeloma            The Paula and Rodger Riney Foundation has been
research in the Institute’s history.                      a strong supporter of Dana-Farber and with this grant
   “The Riney Family are generous and stalwart sup-       has cumulatively donated nearly $60 million to the
porters, and through this grant and their previous        Institute. In 2019, a $16.5 million gift established the
support they continue to make a profound impact on        Riney Family Multiple Myeloma Initiative, which has
scientific discovery and clinical care,” said Laurie      driven groundbreaking research in recent years.
H. Glimcher, MD, president and CEO of Dana-Farber.
“Their leadership will help patients at Dana-Farber
and around the world.”                                       “The Riney Family are generous and
   Multiple myeloma is a challenging cancer that
                                                               stalwart supporters, and through
forms in a type of white blood cell called a plasma
cell. Dana-Farber has been at the forefront of mul-            this grant and their previous support
tiple myeloma therapies over the past two decades,
helping to convert myeloma from a fatal disease to a           they continue to make a profound
chronic condition for many patients. However, thera-
peutic resistance and drug-related toxicities continue         impact on scientific discovery and
to take a toll on many patients, underscoring the need
for innovative treatments.
                                                               clinical care.”
   “My own journey as a myeloma patient – and know-
ing how many others are also living with this disease        – Laurie H. Glimcher, MD

2              Paths of Progress         2022                                  Dana-Farber Cancer Institu te
Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute

Dana-Farber Establishes David Liposarcoma Research Initiative
   Dana-Farber announced in 2021 that The Rossy                 Experimental Therapeutics, and Quick Family Chair
Foundation has committed $10 million to estab-                  in Medical Oncology at Dana-Farber.
lish the David Liposarcoma Research Initiative, a                  “The Rossy Foundation is proud to make this
five-year effort that will spearhead groundbreak-               meaningful contribution toward better treatments for
ing research into liposarcoma at Dana-Farber and                liposarcoma, which affects more than 4,000 patients
external collaborating partner institutions, with               in the United States and Canada every year,” said
the aim of transforming the treatment of this rare,             Gregory J. David, vice-chair of The Rossy Founda-
underfunded, and understudied disease in order to               tion. “Our hope is that this initiative, under the direc-
improve care of patients. The Rossy Foundation and              tion of Dr. George Demetri, will drive breakthroughs
KBF CANADA have partnered to fund the first phase               that not only transform the landscape of liposarco-
of the initiative.                                              ma research, but most importantly help extend and
   This commitment from The Rossy Foundation will               enhance the lives of patients across the globe.”
focus on collaborative research among various                      The David Liposarcoma Research Initiative col-
departments at Dana-Farber – including liposar-                 laboration will start by bringing together teams of
coma biology, biochemistry, immunology, metabo-                 11 principal investigators from four institutions –
lism, genomics, and epigenetics. By conducting                  Dana-Farber, Harvard Medical School, Brigham and
research to improve fundamental understanding                   Women’s Hospital, and the Broad Institute of MIT
of the molecular mechanisms of this disease, the                and Harvard. These investigators will work together
initiative may lead to new approaches to overcome               on an interconnected portfolio of projects that builds
treatment resistance, as well as new strategies for             upon the virtuous cycle of discovery, validation, and
clinical research to improve the outcomes of lipo-              clinical testing with correlative science to stimulate
sarcoma patients worldwide. The overall research                continuous discovery: from bench to patient and
initiative will be led by George Demetri, MD, direc-            back to the lab bench. Dana-Farber will be the lead
tor of the Sarcoma Center, senior vice president for            and coordinating institution for this new initiative.

The David Liposarcoma Research Initiative team includes (from left) Jay Oza, MD, PhD; George Demetri, MD; Suzanne George, MD;
and Candace Haddox, MD.

Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute

New Hale Family Gift Accelerates Pancreatic Cancer Efforts
                                                                                      we are committed to finding a cure.
                                                                                      That would be a wonderful honor
                                                                                      for my husband and legacy for
                                                                                      our family.”
                                                                                         The gift is in honor of Judy’s late
                                                                                      husband, and Rob’s father, Robert
                                                                                      T. “Bob” Hale Sr., a patient of the
                                                                                      Institute who died in 2008. Longtime
                                                                                      supporters of the Institute, Robert
                                                                                      Sr. and Judy Hale established the
                                                                                      Robert T. Hale Sr. and Judy B. Hale
                                                                                      Fund for Pancreatic Cancer Re-
                                                                                      search at Dana-Farber in 2007.
                                                                                         “Working in partnership with
                                                                                      the Hale Family, we have already
                                                                                      made significant progress against
Judy Hale (left), with her son, Rob Hale.
                                                                                      pancreatic cancer,” said Dana-
  Continuing their family’s deep            new imaging approaches and blood          Farber President and CEO Laurie H.
commitment to conquering pan-               tests, and develop new treatments         Glimcher, MD. “We share the Hale
creatic cancer, Judy Hale, her son,         for pre-invasive and early invasive       Family’s bold vision to eradicate
Rob Hale, and his wife, Karen Hale,         pancreatic cancers.                       pancreatic cancer and save lives,
pledged an additional $50 million             The center will also investigate        here and around the world. With
to Dana-Farber in 2021. The gift is         the biology and interplay of pancre-      this incredibly generous, trans-
one of the largest single gifts in the
Institute’s history and supports the
Hale Family Center for Pancreatic
                                                   “Our intention is to substantially speed the pace
Cancer Research, founded in 2016                    of research and new treatments for this
with $15 million from Judy, Rob, and
Karen – bringing the Hale Family’s                  terrible disease.“
cumulative support to Dana-Farber
to more than $80 million.                          – Judy Hale
  The Hale Family gift is enabling
a wide range of ambitious work in           atic cancer cells, the immune sys-        formational gift, the Hale Family is
two main areas of pancreatic can-           tem, and stromal cells, and develop       providing us with an unprecedented
cer research: early detection and           a series of clinical trials to test new   opportunity, and responsibility, to
prevention, and precision medicine          therapies based upon discoveries          do just that.”
and biology. Currently a national           from these initiatives.                     The Hale Family’s commitment
leader in the field, Dana-Farber’s             “Our intention is to substantially     to research and care has continued
Hale Family Center for Pancre-              speed the pace of research and            across the generations. Judy Hale
atic Cancer Research is launching           new treatments for this terrible          created the Hale Family Center for
teams of scientists to leverage             disease,” said Judy Hale, a member        Pancreatic Cancer in 2012, and
health system data to identify per-         of Dana-Farber’s Board of Trustees.       with Rob and Karen, established
sons at highest risk for pancreatic         “We are investing in the exception-       the current Hale Family Center
cancer, detect it earlier through           al talent at Dana-Farber because          for Pancreatic Cancer Research.

4               Paths of Progress           2022                                      Dana-Farber Cancer Institu te
Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute

Dana-Farber Faculty Among World’s Most Highly Cited Researchers
    An examination in 2021 by the Institute for Scien-      Glimcher, MD, president and CEO of Dana-Farber. “By
tific Information at Clarivate named 35 Dana-Farber         deepening our scientific understanding of cancer, we
investigators to the organization’s annual Highly Cited     can improve the level of care for patients everywhere.
Researchers list. The highly anticipated list identifies    I congratulate all of our faculty who were recognized
scientists and social scientists who produced multiple      with this distinct honor.”
papers ranking in the top 1% by citations for their field      The methodology that determines the who’s who of
and year of publication, demonstrating significant          influential researchers draws on the data and analysis
research influence among their peers.                       performed by bibliometric experts from the Institute for
    “Dana-Farber’s talented and devoted investigators       Scientific Information at the Web of Science Group.
are making a tremendous impact on cancer research           Learn more and see the full list at https://recognition.
that is truly felt across the world,” said Laurie H.

Institute Awards $4 Million to Improve Greater Boston
Community Health
  Dana-Farber in 2021 released the first round of           leads several community programs for medically-
funding for its Access to Services awards, aimed            underserved Boston residents focused on eliminating
at ensuring all area residents, particularly those at       disparities in breast, skin, lung, and HPV-related can-
higher risk for developing cancer and other chronic         cers. In addition to the Access to Services grants that
conditions, have access to coordinated and equitable        have been awarded, Dana-Farber has also committed
health and support services. Through this funding           approximately $1 million dollars to the Healthy Neigh-
opportunity, a total of $4 million will be distributed to   borhoods Equity Fund II to address housing needs in
community organizations in Greater Boston over the          Greater Boston. These innovative projects build on
next four years as part of the Institute’s Determination    Dana-Farber’s continuing work to invest in the health
of Need Community Health Initiative process linked to       and well-being of the communities it serves.
Dana-Farber’s new facility in Chestnut Hill.
  In all, 12 nonprofit organizations were awarded
an Access to Services grant to support long-lasting
community health improvement or to boost linkages
to existing health and support services in the region.
  “Funding these innovative projects in Greater Bos-
ton is consistent with our mission, as Dana-Farber
seeks to address the root causes of cancer and other
chronic conditions, while helping to advance health
equity,” said Magnolia Contreras, vice president of
Community Health at Dana-Farber. “By partnering
with local community organizations and working
upstream together, we will increase access to ser-
vices and create the conditions that promote health
for everyone.”
  The Access to Services initiative is managed by
Dana-Farber’s Community Benefits Office, which              Magnolia Contreras, vice president of Community Health

Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute

Dana-Farber Leads 2021 Ranking
of Top 100 Women-Led Businesses
in Massachusetts
   Dana-Farber and its President          most noteworthy companies and
and CEO Laurie H. Glimcher, MD,           nonprofits helmed by women. It
ranked No. 1 in 2021 on the list of       includes health-care organiza-
the top 100 women-led businesses          tions, retail giants, construction
in Massachusetts, as ranked by the        heavyweights, financial institu-
Boston Globe Magazine and The             tions, nonprofits, and more. Taken
Commonwealth Institute, a Boston-         together, the 100 companies on
based nonprofit that supports             the list represent a total revenue
female business leaders.                  and operating budget of more
   Published in November 2021, the        than $66.6 billion. Find the
Top 100 Women-Led Businesses              full list at www.bostonglobe.
in Massachusetts list ranks the           com/magazine.                           Laurie H. Glimcher, MD

Commonwealth Foundation for Cancer Research Gift
Accelerates Joint Research
   The Commonwealth Foundation for Cancer Research            and CEO, Dana-Farber, and director, DF/HCC. ”Their
in late 2021 pledged $25 million to the Bridge Project, a     commitment is a reflection of the world-class innovation
collaborative research program of Dana-Farber/Har-            taking place through the Bridge Project, a collaboration
vard Cancer Center (DF/HCC) and the Koch Institute for        that is changing lives through science. This support will
Integrative Cancer Research at MIT, to transform drug         fund high-impact research and drug development to
discovery and early-stage development.                        offer new solutions to patients.”
   As part of this commitment to the Bridge Project,             The Bridge Project, launched in 2011, funds cross-
The Commonwealth Foundation gift will propel                  institutional and interdisciplinary teams of cancer scien-
“Expansion Grants,” which fund projects being read-           tists, engineers, and clinicians to solve long-standing
ied for clinical testing or that are already in the clinic.   problems in the most intractable cancers. The program
It will also place a significant focus on projects that       was designed to integrate advanced cancer science
accelerate therapeutic drug development, stimulating          research at both institutions by leveraging MIT’s
research on traditionally challenging classes of cancer       strengths in basic cancer research and bioengineering,
drug targets and/or on more conventional targets              and DF/HCC’s strengths in clinical cancer research and
found in rarer forms of cancer.                               cancer care. As such, each team is co-led by at least
   The gift builds on a previous investment of $20 mil-       one MIT investigator and one DF/HCC investigator.
lion in 2015 from the Commonwealth Foundation to the             The Bridge Project links the cancer research efforts
Bridge Project. To amplify the impact of this new gift,       of MIT and DF/HCC – Massachusetts’ two National
DF/HCC and MIT will match these funds over the next           Cancer Institute (NCI)-designated cancer centers.
five years, resulting in a combined $50 million expan-        The Koch Institute is an NCI-designated basic labora-
sion of the Bridge Project.                                   tory cancer center, and DF/HCC is an NCI-designated
   “We are deeply appreciative to the Commonwealth            comprehensive cancer center that unites the cancer
Foundation and the Goodwin Family for their continu-          research efforts of Harvard’s five principal affiliated
ing generosity,” said Laurie H. Glimcher, MD, president       hospitals and two health science schools.

6             Paths of Progress         2022                                      Dana-Farber Cancer Institute
Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute

75 Years of Advancing Cancer Care and Treatment
   Dana-Farber's story begins in 1947 with the first successful treatment of blood cancers by Sidney Farber, MD,
earning him the reputation as the “father of modern chemotherapy.” Now, 75 years later, the combination of
clinical treatment, bench-to-bedside research, and high-quality holistic patient care has made the Institute a
leader in life-changing breakthroughs.
   Some landmarks are noted here, but learn more at

1940s                                                     1990s
Dr. Farber and his team of clinicians and scientists      Dana-Farber becomes a founding member of
are the first to use chemotherapy to attain temporary     the National Comprehensive Cancer Network.
remissions of acute lymphocytic leukemia in chil-         The Institute establishes the nation's first Adult
dren. Research that transfers scientific knowledge        Patient and Family Advisory Council. It becomes
"from the lab bench to the patient bedside" forms         a model for other centers to involve patients and
the foundation for future progress against cancer         loved ones in developing the highest standard of
at the Institute.                                         compassionate health care.

1950s                                                     2000s
Dr. Farber pioneers the concept of patient-centered
                                                          Immunologist Gordon J. Freeman, PhD, discovers
care, in which patients are seen not only by physi-
                                                                   that many cancer cells carry a surface
cians, but also by specialists in other
                                                                   protein called PD-L1, which staves off
areas, such as social work, nutrition, and
                                                                   an attack by immune system T cells.
integrative therapies.
                                                                   This research contributes to insights
                                                                   that help launch a generation of novel
1960s                                                              drugs known as checkpoint inhibitors.
The Children's Cancer Research Founda-
tion (which would later become Dana-
Farber Cancer Institute) develops means                              2010s
to collect, reserve, and transfuse blood-                           A Dana-Farber-led clinical trial leads
clotting factors called platelets to                                to FDA approval of Provenge, the
control bleeding, a common side effect                              first therapeutic cancer vaccine for
of chemotherapy.                                          prostate cancer.
                                                          William G. Kaelin Jr., MD, along with two co-
1970s                                                     awardees, receives the 2019 Nobel Prize for a
Dana-Farber receives federal designation as a             landmark discovery on how the body senses
regional Comprehensive Cancer Center in recogni-          and adapts to changes in oxygen. One result
tion of its excellent multidisciplinary approach to       of the research is the development of new
cancer – including patient care, research, and            cancer drugs.
community outreach.
1980s                                                     Following a clinical trial led by Dana-Farber,
Then-Institute President Baruj R. Benacerraf, MD,         the FDA grants its first approval for CAR T-cell
receives the Nobel Prize for his discoveries in the       therapy for adults with multiple myeloma. The
genetic underpinnings of the human immune system.         therapy trial involving patients whose myeloma
Two out of every three children who enter the Jimmy       had relapsed or become treatment-resistant
Fund Clinic become cancer-free.                           showed rapid responses in most patients.

Progress Paths of - Targeting Cancer Cells With Radiopharmaceuticals - Dana-Farber Cancer Institute
Targeting Cancer Cells With
BY RICHARD SALTUS                 Soon after X-rays were discov-      and long-term side effects.
                               ered in 1895, doctors began using         To maximize the killing power
                               radiation to treat cancer. Today,      of radiation and minimize side
                               about half of all cancer patients      effects, scientists have developed
                               will receive radiation therapy at      ways of attacking cancer cells
                               some point. While it can often be      with radioactive drugs, known
                               highly effective in shrinking tumors   as radiopharmaceuticals, that
                               and alleviating cancer symptoms,       are delivered through the blood-
                               radiation – high-energy beams          stream directly to the tumor. It’s
                               of charged particles – adminis-        an ingenious strategy that poten-
                               tered from outside the body un-        tially can reduce the risk of side
                               avoidably damages some healthy         effects by exclusively targeting
                               tissues and can cause short-           tumor cells. In addition to attack-

8         Paths of Progress   2022                                    Dana-Farber Cancer Institute
CALS   9
“[Right] now, it’s mainly major medical centers and academic sites that are
      set up to use radiopharmaceutical therapy.”

     – Heather Jacene, MD

ing the main tumor, radiophar-           cure cancer but helps to shrink     maceutical efforts are focused
maceutical drugs can also seek           bone metastases and relieve         on radioisotopes that are linked
out and destroy small deposits of        bone pain, and it may help people   to antibodies, peptides (build-
cancer cells that have spread to         with metastatic prostate cancer     ing blocks of proteins), or small
other areas of the body.                 live longer.                        molecules that target specific
   Key elements of radiopharma-             Other radiopharmaceuticals       proteins expressed on the surface
ceutical drugs are radioisotopes         have been approved for thyroid      of tumor cells.
(unstable atoms that emit radia-         cancer, adrenal gland tumors,         In 2018, the FDA approved the
tion) that are guided by molecules       neuroendocrine tumors, and some     drug lutetium Lu 177-dotatate,
such as monoclonal antibodies to         types of non-Hodgkin lymphoma.      or Lutathera, to treat certain
bind to targets present on cancer        Researchers are now designing       gastrointestinal and pancreatic
cells but not normal cells. This         and testing similar compounds       neuroendocrine tumors; Lutathera
brings the radioisotope directly         for cancers including melanoma,     targets the somatostatin receptor
to the tumor, where it acts by           lung cancer, colorectal cancer,     present on the tumor cell surface.
breaking the DNA double helix in         and leukemia. Current radiophar-    The drug’s approval was hailed as
the cancer cells. The potential of
radiopharmaceutical therapy has            Approved Radiopharmaceuticals in Clinical Use
sparked a surge of clinical trials
and commercial activity. There is         Xofigo (radium 223 dichloride) for castration-resistant
“an explosion of companies that           prostate cancer
are looking at different radio-
pharmaceutical agents targeting           Lutathera (lutetium Lu 177 dotatate) for certain digestive
cancer,” says Heather Jacene,             tract cancers
MD, clinical director of nuclear
medicine at Dana-Farber.                  Quadramet (samarium sm 153 lexidronam) to help relieve
   Just in the past few years, a          cancer bone pain
handful of radiopharmaceuti-
cal drugs have been approved              Hicon (sodium iodide I-131) to treat overactive thyroid and
for clinical use. For example,            some thyroid cancers
radium-223 dichloride (Xofigo),
which was approved in 2013 by             Azedra (iobenguane I-131) for adrenal gland tumors and a
the U.S. Food and Drug Adminis-           rare nerve cell tumor
tration (FDA), can be used to treat
prostate cancer that has metas-           Zevalin (ibritumomab tiuxetan) for certain types of
tasized to the bones. Radium-223          non-Hodgkin lymphoma
dichloride is absorbed into the
                                          Numerous other radiopharmaceuticals are in development
bones, and the radiation it emits
kills cancer cells there. It does not
                                          and/or in clinical trials.

10            Paths of Progress         2022                                 Dana-Farber Cancer Institu te
Heather Jacene, MD, clinical director of nuclear medicine, oversees treatment with a radiopharmaceutical drug, which contains
a radioactive substance to kill tumors.

a big step forward in the field: It         cancer cells.) The images can               the treatment improved the time
showed that solid tumors could be           show whether prostate cancer                it took for the cancer to progress
effectively targeted with cell-kill-        has spread to other parts of                and the overall time that patients
ing radiation from radioisotopes            the body.                                   were able to live with cancer.
linked to peptides that latched               As an experi-                                             “It is impressive
onto a cancer-specific target on            mental treatment,                                         because it is targeted
tumor cells.                                researchers at the                                        therapy, and most
   Advanced prostate cancer has             drug company No-                                          other prostate cancer
been an early testing ground for            vartis developed a                                        drugs aren’t target-
radiopharmaceuticals. In 2020, the          radiopharmaceuti-                                         ed,” said Mary-Ellen
FDA approved a diagnostic drug              cal drug called                                           Taplin, MD, a prostate
that, when injected into the blood-         Lu177-PSMA-617                                            cancer specialist and
stream, can be imaged by PET                that targeted                                             chair of the Executive
scanning to indicate the presence           PSMA and was                                              Committee for Clinical
of PSMA-positive prostate cancer            delivered via the                                         Research at Dana-
lesions in the tissues of the body.         bloodstream to men with ad-                 Farber. “I am thrilled to have an-
(PSMA, or prostate-specific mem-            vanced prostate cancer. Report-             other option for patients who are
brane antigen, is a protein found           ing on a phase 3 study in June              in need of effective treatments.”
in large amounts on prostate                2021, the study team reported that             Taplin says the added survival

Jacene, who is also assis-
                                                                                     tant chief of nuclear medicine
Mary-Ellen Taplin, MD, presents radiopharmaceutical study results at a conference.   molecular imaging at Brigham
                                                                                     and Women’s, says several trials
benefit – about four months                 cancer in the body, coupled with         of radiopharmaceuticals are un-
on average – “shows that this               another radiotherapeutic drug to         derway at Dana-Farber. She says
treatment, while effective, can             treat it is known as theranostics.       clinical trials may be suggested
be improved upon to bring more                  “The field of theranostics has       by medical oncologists in treat-
benefit to our patients.” This              seen substantial growth recently         ment centers or in nuclear medi-
radiopharmaceutical drug could              with the approval of several new         cine. “In either instance, together
show more advantages in                     agents,” said Ross Berbeco,              the treatment center team and
patients with earlier stages of             PhD, the director of medical             our nuclear medicine team evalu-
the disease or as part of combi-            physics research in Radiation            ate the proposal to determine if
nation therapy. These approach-             Oncology. “At Dana-Farber and            it is something that fits within our
es are being studied actively in            Brigham and Women’s Hospital,            portfolio and makes scientific
clinical trials.                            it is emerging as a potentially          sense.” Through this approach,
   Using a radioactive substance            important addition to our cancer         Dana-Farber participated in a
that can be imaged to locate a              treatment options.”                      pivotal phase 3 study that led to
                                                                                     the approval of Lu177-dotatate,
                                                                                     as well as the phase 3 study of
     “I am thrilled to have another option for patients                              Lu177-PSMA-617.
                                                                                         One recently opened trial is a
      who are in need of effective treatments.”
                                                                                     phase 1 study that uses an alpha-
                                                                                     particle-emitting isotope drug
     – Mary-Ellen Taplin, MD                                                         to target IGF-1R (the insulin-like

12             Paths of Progress          2022                                       Dana-Farber Cancer Institu te
Target                                           with radioactive substances.
                                                                     Protein                                             Another challenge that re-
                                                                                                                      searchers are grappling with
                                                                                                                      is dosimetry – calculating how
                                                                                                                      much of a radioactive drug to
                                                                                                                      give to an individual patient
                                                                                                                      and for how long. Jacene says

                                                       Linker                                                         that greater study of dosimetry
                                    Radioactive                  Targeting                                            should help personalize therapy
                                    Compound                     Molecule                                             for patients. In addition, the need
                                                                                Cancer Cell                           for large numbers of specialized
                                                                                                                      practitioners and staff qualified to
                                Radiopharmaceuticals consist of a radioactive molecule, a targeting molecule, and     handle and administer radiophar-
                                a linker that joins the two. Source: National Cancer Institute                        maceuticals imposes limits on
                                                                                                                      how widely the treatments will be
                                growth factor-1 receptor) on solid             pharmaceutical and other types         used in the near future.
                                tumor cells, including prostate,               of drugs, such as targeted kinase         “I think, and truly hope, the
                                colorectal, and adrenocortical                 inhibitors and immunotherapy           field continues to grow, but right
                                cancers. “You have to get im-                  agents, to be potentially more         now it’s mainly major medical
                                aged first, and if your tumor has              effective than radiopharmaceuti-       centers and academic sites that
                                a high enough level of IGF-1R you              cal agents alone.                      are set up to use radiopharma-
                                can go onto the next phase get-                   Despite the potential and           ceutical therapy,” Jacene says.
                                ting treated,” explains Jacene.                advantages of radiopharmaceuti-        However, she says, the field is
                                “If it’s there, we can treat it.”              cal treatment, the field is still in   becoming better known and this
                                   Another trial is testing a com-             its early days. It has been tested     extends to patient groups as well.
                                bination of radium-223 dichloride              in only a few of the many types           “I attended a prostate cancer
                                and cabozantinib, a targeted                   of cancer that exist, and much         support group last month and
                                inhibitor drug, in patients with               remains to be explored in terms        I was asked extremely important
                                advanced kidney cancer that has                of targets that can be attacked        and tough questions [about
                                metastasized to bones.                                                                the therapy] for 30 minutes,”
                                   In collaboration with Jennifer                                                     Jacene says.
                                Chan, MD, MPH, director of the                                                           To stimulate research and
                                program in carcinoid and neuro-                                                       collaboration on promising
                                endocrine tumors at Dana-Farber                                                       new radiopharmaceuticals, the
                                Brigham Cancer Center, the                                                            National Cancer Institute (NCI) in
                                nuclear medicine team is partici-                                                     2019 launched the Radiopharma-
                                pating in a cancer cooperative                                                        ceutical Development Initiative,
                                group clinical trial for patients                                                     headed by Charles Kunos, MD,
                                with neuroendocrine tumors. The                                                       PhD, of NCI’s Cancer Therapy
                                patients receive the radiophar-                                                       Evaluation Program. He predicts
                                maceutical Lu177-dotatate, along                                                      that this new targeted approach,
                                with triapine, a drug that primes                                                     while it won’t eliminate conven-
                                cancer cells to be more respon-                                                       tional radiation therapy, “is going
                                sive to radiation. Researchers                                                        to transform radiation oncology
                                expect combinations of radio-                Ross Berbeco, PhD                        in the next 10 to 15 years.”

14   Paths of Progress   2022   Dana-Farber Cancer Institute
Mapping the Intestinal Microbiome for Clues About Cancer
                             BY ROBERT LEVY

  It’s a jungle in there. The human colon, or large intestine, is home
to one of the densest, most diverse collections of microorganisms on the
planet. Consisting of trillions of bacteria cells in hundreds of species, along
with untold numbers of viruses, parasites, and fungi, these wee forms of
wildlife, collectively known as the intestinal microbiome, are involved in
everything from digesting food to regulating the immune system.

“The totality of the implications of the microbiome                               and cancer received a powerful
                                                                                       push in 2019 with the awarding
      for cancer is grand – from prevention to treatment –                             of a $25 million Grand Challenge
                                                                                       grant from Cancer Research UK, a
      and as such we have a grand challenge before us.”                                charity based in the United King-
                                                                                       dom, to an international team of
     – Wendy Garrett, MD, PhD                                                          14 scientists. The program’s focus
                                                                                       is explicit in its name: Opportunity
   The possibility that the microbi-     communicate with the brain.                   to Investigate the Microbiome’s
ome plays a role in colon cancer            “The totality of the implications          Impact on Science and Treatment
– as either a promoter or inhibi-        of the microbiome for cancer is               In Colorectal Cancer, or OPTIMIS-
tor – has fascinated scientists for      grand – from prevention to treat-             TICC. Its goal is ambitious: to
years. Cancer is notorious for           ment – and as such we have a                  pinpoint how the microbi-
altering its environment to suit         grand challenge before us,” says              ome impacts the onset and
its needs: coaxing other cells to        Wendy Garrett, MD, PhD, of Dana-              development of colorectal
soften up nearby tissue so tumor         Farber’s Center for Gastrointesti-            cancer and to use those
cells can slip through, for example,     nal Oncology and of the Harvard               findings to improve outcomes
or pacifying immune system cells         T.H. Chan School of Public Health             for people with the disease. Its
that normally would attack a             and co-director of the Harvard                leaders are Garrett and Matthew
tumor. It would be very un-cancer-       Chan Microbiome Public Health                 Meyerson, MD, PhD, director of
like for colon tumors not to try to      Center, whose research focuses                Dana-Farber’s Center for Cancer
       make use of the bacterial         on the interactions between                   Genomics.
        and microbial riches in their    microbes and their hosts and how                 The program brings together the
        vicinity. It would be equally    those interactions may affect                 elements – data, tissue samples,
     surprising if at least some         inflammatory bowel diseases                   and scientific talent – needed
of those microbes – so various           and cancer.                                   for a sustained assault on the
in their functions and behavior –           The study of the relationship              question of whether the micro-
didn’t exert a restraining force         between the intestinal microbiome             biome impacts cancer and, if it
on cancer.
   Research into the relationship of
colon cancer and the microbiome
has boomed in recent years as
technology has enabled investi-
gators to survey the occupants
of the colon with unprecedented
precision and scientists have
gained a deeper understanding
of the microbiome’s role in overall
health. Once viewed primarily as a
workforce for breaking down fiber
and certain carbohydrates in food
and producing substances like
vitamins B12 and K, gut bacteria
                                         Faecalibacterium prausnitzii bacteria (shown above) is one of the most abundant
also stop harmful bacteria from          bacterial species found in the human gut. Its presence is thought to give protection
overrunning the intestine, prevent       against a number of gut disorders, including inflammatory bowel disease, Crohn’s
certain allergies, and even              disease, and colon cancer.

16            Paths of Progress         2022                                          Dana-Farber Cancer Institu te
Wendy Garrett, MD, PhD (left), and Matthew Meyerson, MD, PhD, focus on the interactions between microbes and their hosts and
how they may affect colon cancer.

does, how that relationship can be        impact, positively or negatively,           questions about how environmen-
manipulated to help patients.             on the effectiveness of treatment           tal factors shape the microbiome
   “We have computational biolo-          and the side effects of various             and influence treatment response.”
gists, cancer genomicists, clinical       therapies.
trial leaders in colon cancer,               “With MICROCOSM, we estab-               New Tools to Identify
epidemiologists, immunologists,           lished an infrastructure to collect         Intestinal Microbes
and microbiologists on a dream            these samples and generate data                Though scientists have specu-
team that can focus like a laser          from them – on the genetic makeup           lated about a link between the
on colon cancer and the microbi-          of the tumor cells and bacteria             microbiome and colon cancer for
ome,” Garrett says. “It’s a thrilling     cells, on the type of immune system         ages, it is only relatively recently
and transformative opportunity            cells mixed in with them – and real-        that technology has handed them
for microbiome science and for            ly begin to crack whether there’s a         the tools needed to obtain a defini-
our patients.”                            link between the microbes that live         tive answer. A key advance was
   The program’s clinical flagship        in a person’s gut, in their tumor, and      Meyerson’s development in the
study, known as MICROCOSM (for            their response to treatment,” says          early 2000s of a method called
MICRObiome of Colorectal Cancer:          Kimmie Ng, MD, MPH, co-director             sequence-based computational
Longitudinal Study of Mechanism),         of the Colon and Rectal Cancer              subtraction. Though its name
is collecting long-term health            Center and director of the Young-           is a mouthful, the concept
information and tissue and stool          Onset Colorectal Cancer Center at           is simple: collect a stool
samples from more than 2,500              Dana-Farber, as well as a member            sample from an individual,
people across North America and           of the OPTIMISTICC team that is             sequence the DNA of all the
Europe who were being treated             co-leading MICROCOSM. “And                  cells within it, and subtract out
for colorectal cancer. Research-          layered on top of that, we’ll have          the human DNA. What’s left is the
ers are not only exploring whether        data on everything from where               DNA of intestinal microbes – bac-
the microbiome plays a role in the        participants live to what they eat          teria, viruses, fungi, and parasites.
formation or growth of colorectal         to how much they exercise, which               The approach was powerful in
cancer but also whether it has an         will help us answer a wide range of         principle, but the DNA-sequencing

MD, PhD, now at Brigham          good environment for them? Or is
                                                and Women’s Hospital,            it some combination of the two?
                                                that indicated that patients     Despite a lot of research in the
                                                whose colorectal tumors          field, we really don’t have a clear
                                                harbored high levels of          answer to that question.”
                                                Fusobacterium had worse
                                                prognoses than those             Finding the Cancer-
                                                whose tumors had lower           Microbiome Link
                                                levels of the bug. A 2017           To truly make the case that the
                                                study led by Meyerson and        microbiome has an impact on
                                                co-authored by Ng and            colorectal cancer or the effec-
                                                Giannakis found that when        tiveness of therapies, it would be
                                                colorectal cancer cells          necessary to find a mechanistic
Kimmie Ng, MD, MPH (left), examines a     metastasize to other parts of the      connection – a chain of interac-
patient at the Colon and Rectal Cancer    body, the roving cells brought         tions by which gut microbes alter
Center at Dana-Farber.
                                          along some of their bacterial          the behavior of tumor cells
technology of the time didn’t have        cronies from the colon, including      and the immune cells in
the capacity to process large-            Fusobacterium nucleatum, like          their vicinity. Both Garrett
enough numbers of cells. About a          mementos from home. In studies         and Giannakis, who is also
decade later, Aleksandar Kostic,          with animal models carrying the        a member of the OPTI-
a PhD student in Meyerson’s lab           metastatic cells, the researchers      MISTICC team, are at the
(and now a researcher at Joslin           found that treating the animals        forefront of these efforts.
Diabetes Center), created a               with an antibiotic that targets           In her lab at the Harvard T.H.
more powerful system, called              many bacteria, including Fusobac-      Chan School, Garrett is probing
PathSeq, that uses next-gen-              terium, caused tumor cell prolif-      the microbiome/colon cancer
eration sequencing. With it, he
analyzed colon cancer samples                   “What we don’t know yet is do these bacteria
to see what types of bacteria
were present.                                    actually provoke the growth of the cancer or
  In a study published in 2011,
Meyerson, Garrett, Kostic, and                   are they merely opportunistic.”
colleagues at Dana-Farber and
the Broad Institute of MIT and                  – Matthew Meyerson, MD, PhD
Harvard reported that they’d
found strikingly high levels of the       eration to decline.                    nexus with the biological equiva-
bacterium Fusobacterium nuclea-              Findings like these point to an     lent of a clean slate. Working
tum in colorectal cancers. What           association between certain gut        with “gnotobiotic” mouse mod-
     made the discovery par-              bacteria and tumors of the colon.      els – animals that are utterly
        ticularly notable was that        But as scientists are quick to point   microbe-free – Garrett and her
        Fusobacterium is usually          out, association is not causation.     colleagues are implanting the
        found in the mouth, not           As Meyerson puts it, “What we          animals with specific sets of in-
      the bowel.                          don’t know yet is do these bacte-      testinal microbes to identify which
  The study was followed by               ria actually provoke the growth of     of them, if any, have an effect on
another, by Meyerson, Garrett,            the cancer or are they merely op-      colon cancer.
and Marios Giannakis, MD, PhD,            portunistic: are they there primar-      “We’ve studied Fusobacterium
of Dana-Farber, and Shuji Ogino,          ily because the cancer provides a      and how it might influence the

18             Paths of Progress         2022                                    Dana-Farber Cancer Institu te
“We’re particularly interested in finding ways to                                He acknowledges that microbiome
                                                                                 research is still in its infancy and
    improve the effectiveness of immunotherapy in                                that much remains to be discovered.
                                                                                 “We’re still very much in the descrip-
    colon cancer.”                                                               tive stage,” he says. “In many ways
                                                                                 the intestine is terra incognita. We’re
   – Marios Giannakis, MD, PhD                                                   trying to find out what species are
                                                                                 there, in what proportions, and who
immune system in creating condi-       connective tissue, along with             they cohabitate with.”
tions that promote cancer in the       normal and colon cancer cells,               But if researchers uncover a
colon,” Garrett remarks. “We’ve        enable scientists to zoom in on           definitive connection between
studied not only fusobacterial         the interactions between specific         the microbiome and colon cancer,
metabolic products to see how          cell types.                               the consequences for prevention
they contribute to colon cancer,          “We’re particularly interested         and treatment of the disease could
but also microbial metabolites that    in finding ways to improve the               be profound.
hinder colon cancer development.       effectiveness of immunotherapy                  “If we find a unique microbial
We’re very interested in diet at the   in colon cancer,” Giannakis                   signature in people who later
molecular level. With Dr. Kimmie       says. Immunotherapies have                    develop colon cancer, we could
Ng and her group, we’ re working       been less successful against              potentially create a screening or
to identify associations between       colorectal cancer than other forms        early-detection test that would be a
dietary micronutrients and the         of cancer. “Does the microbiome           lot less invasive than current tech-
microbiome in the colon. The goal      affect the immune system in ways          niques,” Ng comments. “If we
is to pull apart their mechanistic     that hamper immune-stimulating            can nail down what the predictors
links using tools like gnotobiotics    therapies?” Giannakis asks. “If           of treatment response are, we
to develop microbiome-targeted         that’s the case, can we modify the        may be in a position to alter the
therapies that we can bring back       microbiome to reap the benefits of        microbiome to produce better
to patients.”                          these treatments?”                        results for patients.”
   One area of interest under-
scores just how much remains to
be learned about the microbiome:
where, in relation to all the other
cells in the intestinal environ-
ment is the microbiome located
and how does it interact with
neighboring cells? To find out,
Giannakis and his colleagues are
studying colorectal tumors at the
single-cell level to produce an
“atlas” of the disease. They’re
also developing three-dimensional
laboratory models of colorectal
cancer in hopes of simulating the
conditions of the colon and its
environment. The models, which
include immune system cells,           Marios Giannakis, MD, PhD, researches the impact of gut microbes and how they
stromal cells like those found in      affect tumor cells and the immune system.

20   Paths of Progress   2022   Dana-Farber Cancer Institute
The Enduring Legacy of
                    David Livingston, MD
                                                BY RICHARD SALTUS

  Dana-Farber’s David Livingston, MD, was a titan           tory also examined how defects in various tumor
among the giants of cancer research. When he died           suppressor loci regulate cell proliferation, genome
unexpectedly on Oct. 17, 2021, at age 80, he left a leg-    integrity, and cell survival. David Livingston was a
acy of groundbreaking insights into the development         brilliant translational researcher whose understand-
of cancer, especially breast and ovarian cancers.           ing of molecular biology and genetics led to enduring
Equally important for the future of the field, he trained   improvements in the research and treatment of breast
scores of students and postdoctoral fellows, many           and ovarian cancer.”
of whom, inspired by his rigorous scientific methods           His early work focused on how the DNA tumor virus
and his passion for improving cancer treatment,             SV40 caused cancer. His lab showed this involved
are working at Dana-Farber and other elite research         inactivation of the protein encoded by the tumor sup-
centers and hospitals around the world to fulfill           pressor gene RB1, which, when defective, can lead to
his vision.                                                 retinoblastoma, a rare cancer of the eye in children.
  In a research career spanning more than 50 years,         Later, Livingston also worked on the BRCA1 and
highlights included Livingston’s landmark insights          BRCA2 tumor suppressor genes that contain the blue-
into how mutations in the BRCA1 and BRCA2                   print for BRCA proteins. The BRCA proteins are criti-
genes can dramatically raise the risk of breast and         cal to repairing DNA damage, among other functions.
ovarian cancer.                                             When a mutant version is inherited, the malfunction
  “Collectively, [Livingston’s] research has revo-          of the DNA repair system markedly increases the
lutionized the mechanisms by which malignancies             lifetime risk of breast and ovarian cancer.
such as breast and ovarian cancer are understood,              The roles of the mutant BRCA1 and BRCA2 proteins
prevented, and treated,” the American Association           in causing tumors “are derived in large part from their
for Cancer Research said in a statement. “His labora-       function as mediators of the DNA repair process of

homologous recombination, and
David’s lab was the first to make
this connection,” says Robert
Weinberg, PhD, a pioneering
cancer researcher at MIT and the
Broad Institute. “He proposed that
the genomic destabilization that
occurs when one of these pro-
teins is lost from the repertoire of
mammary cells is a driving force
of BRCA-linked tumorigenesis. At
the time of his passing, David’s lab
was actively engaged in revealing
new aspects of BRCA1 function.”

A Legacy of Mentoring
   Livingston was the Emil Frei
                                         David Livingston, MD (left), reviewing Jimmy Fund Building renovation plans with
III Distinguished Professor of
                                         longtime Dana-Farber staff member Thomas McNamara.
Medicine and Genetics at Harvard
Medical School (HMS) and the             mentored nearly 200 fellows and             is the director of the Center for
Charles A. Dana Chair in Human           students in his laboratory. In many         Functional Cancer Epigenetics at
Cancer Genetics at Dana-Farber,          cases, after moving on to open              Dana-Farber, and the current Emil
where he had been on the faculty         their own labs, these scientists            Frei III Professor of Medicine at
since 1973.                              have been inspired by their work            HMS. “His trainees populate the
   Equally important as his discov-      with Livingston to continue dis-            scientific leadership of many of the
eries was the immense impact             secting the thorny mysteries of             world’s major medical centers.”
Livingston had by recruiting and         BRCA1 and BRCA2.                               Perhaps his most famous pro-
training some of the brightest             “His many trainees who are                tégé is Dana-Farber’s William G.
young scientists, many of whom           now faculty at Harvard Medical              Kaelin Jr., MD, who Livingston was
have gone on to prestigious              School and around the world                 able to see share in the 2019 Nobel
faculty positions. By one count, he      will continue to build on his work          Prize for Medicine for discoveries

                                           ”Collectively, his research has revolutionized the
                                            mechanisms by which malignancies such as
                                            breast and ovarian cancer are understood,
                                               prevented, and treated.”

                                               – American Association for Cancer Research

                                         and will ultimately be his endur-           about how the body senses and
                                         ing legacy,” says Myles Brown,              adjust to changing oxygen levels in
David Livingston, MD, reviewing study    MD, a breast cancer researcher              the environment. The findings have
slides in his office.                    who trained with Livingston and             already led to practical applica-

22             Paths of Progress        2022                                         Dana-Farber Cancer Institu te
tions, including new drugs to            “His many trainees who are now faculty at Harvard
treat cancer.
   Other former Livingston trainees       Medical School and around the world will continue
who are HMS professors include
James DeCaprio, MD, chief of the          to build on his work and will ultimately be his
Division of Molecular and Cellular
Oncology at Dana-Farber; James
                                          enduring legacy,”
Griffin, MD, professor of Medicine
at HMS and a leukemia expert
                                           – Myles Brown, MD
at Dana-Farber; William Sellers,
MD, former global head of oncol-      training with Livingston, she                impaired in their ability to repair
ogy at the Novartis Institutes for    completed a short residency;                 this damage, thus raising the risk
BioMedical Research and senior        and then, again with his support,            of a cell becoming cancerous.
advisor to the president for ex-      earned an NIH Director’s Early               “But we still don’t entirely under-
perimental therapeutics at Dana-      Independence DP5 award and a                 stand how loss of BRCA1 function
Farber; Ralph Scully, MBBS, PhD,      coveted Harvard faculty appoint-             leads to cancer,” notes Hill.
professor of Medicine at HMS and      ment with her own lab. Thanks
co-director of the Program in DNA     to Livingston’s influence, Hill’s lab        Fostering Collaboration
Repair and Genomic Instability        is studying, among other things,               Livingston was born in Cam-
at the Cancer Research Institute,     how BRCA mutations cause                     bridge, Mass., and educated at
Beth Israel Deaconess Medi-           ovarian cancer.                              Exeter, Harvard University, and
cal Center (BIDMC); and Daniel           The proteins made using the               Tufts University School of Medi-
Tenen, MD, professor of Medicine      instructions in the BRCA genes               cine, after which he completed
at HMS and BIDMC.                     are part of a protein complex                training in internal medicine at the
   The most recent graduate of the    that repairs DNA when both                   Peter Bent Brigham Hospital. His
Livingston lab to join the Harvard    DNA strands in a cell are broken.            postdoctoral training was at the
faculty is Sarah Hill, MD, PhD,       Mutant BRCA proteins are                     National Institutes of Health and
who now has her own laboratory
at Dana-Farber studying ovarian
cancer. “I owe my career to him,”
she says.
   Hill began working with Liv-
ingston in 2001, when she was an
18-year-old freshman at Harvard
College assigned to Livingston
as a mentee. She was quickly
impressed and asked if she could
do her undergraduate thesis
research in his lab. She did, and
with his support subsequently
went to Oxford University as a
Rhodes Scholar before returning
to enter the MD-PhD program at
Harvard, where she completed
her PhD in Livingston’s lab study-
ing BRCA1. After her MD-PhD           David Livingston, MD, presenting at an NCI visit to Dana-Farber.

Left photo: David Livingston, MD (left), Emil Frei III, MD (middle), and Lee Nadler, MD. Right photo: David Livingston, MD (left),
Daniel Vasella, CEO of Novartis (middle), and Edward J. Benz Jr., MD (right), at the Sidney Farber Awards.

HMS, before being recruited to                that resulted in the development               wrote a long, personal essay in
Dana-Farber.                                  of PARP inhibitors that are                    the journal Cell. “David methodi-
   After the isolation of the breast          used to treat breast and ovarian               cally sculpted me into a scientist
cancer susceptibility gene BRCA1              cancers from people with                       (and talked me out of quitting
in 1994, there was uncertainty                BRCA1/2 mutations.”                            at least six times while I was in
about where in the cell the BRCA1                Judy Garber, MD, MPH, was                   his laboratory, when the work
protein carried out its functions.            one of the principal investigators             seemed too frustrating and hard),
“David’s group was one of the                 of the OlympiA trial that recently             and his mentorship and advocacy
first to make monoclonal antibod-             reported a disease-free survival               for me continued almost until
ies that answered the question                benefit for BRCA1/2-mutant breast              the very day that he died,” wrote
of where the BRCA1 protein was                cancer treated with the PARP                   Kaelin. “My eventually winning
localized, and the Livingston                 inhibitor olaparib, says Brown.                the Nobel Prize says more about
group determined in a landmark                Garber, who leads Dana-Farber’s                David than it does about me.”
paper that it is located in the cell’s        Cancer Genetics and Prevention                    Invariably, the memorial essays
nucleus,” Hill explains. As a re-             program, wasn’t one of David’s                 described Livingston’s ground-
sult, “you could finally ask: What            trainees, but she was a very close             breaking efforts to foster collabo-
does BRCA1 do? The antibodies                 collaborator over the years and                ration among scientists, from his
used in those experiments were                worked to translate Livingston's               larger institutional accomplish-
so critical, and people are still us-         work to the clinic.                            ments to the informal retreats at
ing them constantly.”                            After Livingston’s death, many              the Livingston family farm for the
   Brown says that Livingston’s               leading scientific journals pub-               purpose of open sharing of unpub-
work identifying the role of                  lished obituaries or appreciations             lished research findings – and
BRCA1/2 in DNA damage repair                  penned by his colleagues and for-              always accompanied by memo-
“was the fundamental discovery                mer trainees. Kaelin, for example,             rable meals and stories served up

24              Paths of Progress           2022                                             Dana-Farber Cancer Institu te
by the prominent          “David methodically sculpted me into a scientist
               scientists at
               the retreats.              (and talked me out of quitting at least six times
                 “David was
               instrumental in            while I was in his laboratory when the work
               bringing people
               together in the fight
                                          seemed too frustrating and hard), and his
               against cancer, and        mentorship and advocacy for me continued
               he led the effort to
               establish the Dana-        almost until the very day that he died.”
               Cancer Center (DF/
               HCC),” wrote Brown         – William Kaelin Jr., MD
               and DeCaprio in an
               obituary in Nature.
               “In doing so, he        tration-approved targeted cancer          and ovarian cancer – and possibly
               brought together        therapies,” they said.                    to prevent them.
               a prestigious yet          More recently, Livingston                “He used to say to us, there are
               somewhat reluctant      worked with Tyler Jacks, PhD, at          women in the hospital here who
group of leaders and investigators     MIT to develop the Bridge Project,        are so sick and losing their hair –
from seven Harvard institutions        a collaboration between DF/HCC            we have to do something better
and served as its deputy director      and the Koch Institute for Integra-       for this disease,” says Hill. “I
from 1999 to 2019.”                    tive Research at MIT. Bridging the        think he would have found ways
   Brown and DeCaprio also noted       Charles River geographically and          to detect cancers early and how
that Livingston was instrumental       different disciplines metaphori-          to prevent them. Making sure
in forming an academic-industry        cally, it brings together cancer          David’s legacy is honored is a
partnership between Dana-Farber        researchers and bioengineers              huge thing for everyone who
and Sandoz (now Novartis) in the       from MIT with clinical oncologists        worked with him.”
early 1990s that has continued         from Harvard’s hospital consor-             That is also true for Dana-
ever since. “David’s vision played     tium to address pressing prob-            Farber President and CEO Laurie
a key role in the development of       lems in cancer care.                      H. Glimcher, MD, who, although
several Food and Drug Adminis-            Sarah Hill, who says she talked        she was not one his trainees,
                                                     to Livingston the Fri-      expressed the feelings of many
                                                     day before the week-        when she said, “We have lost
                                                     end on which he died,       not just a source of comfort but
                                                     said she is still deeply    a source of inspiration. David
                                                     saddened by his             Livingston made it possible for us
                                                     passing, but continues      to dream big about the future of
                                                     to be inspired by his       Dana-Farber, because that was
                                                     zeal for research and       how he saw it, and his unflag-
                                                     ambition to improve         ging enthusiasm and love for the
                                                     treatments for breast       institution and everyone in it lifted
                                                                                 our hearts and spirits every day.
                                                    Ursula Matalonis, MD
                                                    (left), Joyce Liu, MD        Surely, there is no better way to
                                                    (middle), and David          honor his memory than to do what
                                                    Livingston, MD               he spent his life doing.”

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