Henri and Belinda 
Termeer
Program
in Systems Pharmacology 

Benefactor Report

March 2024

 March 29, 2024

 Mrs. Belinda Termeer
396 Ocean Avenue
Marblehead, MA 01945-3837

Dear Belinda,

It’s my pleasure to share the enclosed report on the Henri and Belinda Termeer Program in Systems Pharmacology at Harvard Medical School. I trust you’ll find great interest in exploring the innovative pursuits supported by your funding, which enables scientists in the Laboratory of Systems Pharmacology (LSP) to, among other endeavors, delve into a more profound comprehension of cancer and the mechanisms underlying cancer drug efficacy.

As you’ll read in the report, Dr. Caitlin Mills is using Termeer Program funding to blaze a trail in polypharmacology—the concept of pharmaceutical agents acting on multiple disease pathways or targets simultaneously. Previously, she identified potential kinase targets for the prevention of neurodegeneration in a subset of patients with Alzheimer’s disease and for the prevention of chemotherapy-induced peripheral neuropathy. In the past year, Dr. Mills and her collaborators have explored these identified targets in more depth. She has also worked with collaborators to explore the potential of CDK7 inhibition for treating ovarian cancer. Meanwhile, the Dye Drop method that she developed has been used to profile the effects of targeted and immune-modulating therapies on models of melanoma, as well as to explore novel targets and DNA-damaging agents in glioblastoma.

Dr. Genevieve Boland, whose lab at MGH leads correlative immuno-oncology efforts in melanoma and gastrointestinal malignancies, has worked with the LSP—supported by Termeer Program funding—toward characterizing tumor-immune interactions, tumor evolution over time, and features of high-risk biology as potential biomarkers to impact therapeutic decision-making.

Thank you, again, not only for establishing the Termeer Program but also for your service as co-chair of the Discovery Council and as a member of the Board of Fellows. I look forward to seeing you at the upcoming Board meeting and dinner.

Dr. Mills is the director of preclinical pharmacology in the Harvard Program in Therapeutic Science. She is also a lecturer on systems biology in the Blavatnik Institute at Harvard Medical School. Her research interests include prediction of breast and ovarian cancer drug response, kinase inhibitor polypharmacology, and high throughput phenotypic screening. She also mentors graduate students and early-career technicians.               

Dr. Mills  joined the Laboratory of Systems Pharmacology (LSP) in the fall of 2014 to further pursue her interest in breast cancer research. Since uncovering important functional secondary targets of CDK4/6 inhibitors, a breakthrough family of drugs for recurrent hormone-positive breast cancer, Dr. Mills has expanded her research program to new drug classes and cancer types.  

The common thread in the projects Dr. Mills has led and supported in the past year is polypharmacology—which drugs hit which targets, and which targets matter in various biological contexts? She previously leveraged the LSP Optimal Kinase Library to deconvolve complex polypharmacology and identify potential kinase targets for the prevention of neurodegeneration in a subset of patients with Alzheimer’s disease (AD). She also sought kinase targets for the prevention of chemotherapy-induced peripheral neuropathy (CIPN). In the past year, Dr. Mills has collaborated with Veselina Petrova, PhD, a postdoctoral fellow in the lab of Clifford Woolf, MB, BCh, PhD, at Boston Children’s Hospital, to explore the identified targets more deeply.  

For the AD work, Dr. Mills’ team launched a medicinal chemistry campaign to develop new agents with high affinity for the team’s target of 

Description of Work

Works Cited

 interest that are brain penetrant. Dr. Mills has been testing these candidate agents in a cell-based model system of AD to help inform which molecules to pursue further. For the peripheral neuropathy work, Dr. Mills has helped to identify a set of selective tool compounds to target the kinases of interest and test them in model systems to

​understand the mechanism(s) underlying their neuroprotection. A critical consideration in the development of drugs to mitigate CIPN is that the drugs do not interfere with the efficacy of the chemotherapeutic on cancer. Therefore, Dr. Mills has counter-screened all candidate drugs on cancer cell lines. 

Given the clinical success of CDK4/6 inhibitors for the treatment of breast cancer, the LSP is interested in targeting other cell cycle proteins. Dr. Mills has been collaborating with Nathanael Gray, PhD, of Stanford University, and Panos Konstantinopoulos, MD, PhD, of Dana-Farber Cancer Institute to explore the potential of CDK7 inhibition for treating ovarian cancer. Targeted

​therapies are often limited by response durability due to acquired drug resistance. With this in mind, Dr. Mills has been working to understand how resistance to CDK7 inhibition can arise, with the goals of identifying a biomarker for patients more or less likely to develop resistance and identifying treatment strategies to delay or prevent the acquisition of resistance.

As director of preclinical pharmacology in the Harvard Program in Therapeutic Science, Dr. Mills has continued to support dose-response studies in the LSP by providing access to the Dye Drop method that she developed1. This method accurately measures the effects of drugs of interest on cell viability and cell state. In a single experiment, users can answer several important questions about what their drugs are doing to cells. In the past year, the assay has been used to profile the effects of targeted and immune-modulating therapies on models of melanoma2 and to explore novel targets and DNA damaging agents in glioblastoma. 

1. Mills, C. E. et al. Multiplexed and reproducible high content screening of live and fixed cells using Dye Drop. Nature Communications 13, 6918 (2022). 

2. Sun, Y. et al. Targeting TBK1 to overcome resistance to cancer immunotherapy. Nature 615, 158–167 ​

Dr. Boland is an HMS associate professor of surgery at Massachusetts General Hospital (MGH) and vice chair of research for the Department of Surgery at MGH, where she is also section head of melanoma/sarcoma surgery, director of the Therapeutic Intralesional Program, and surgical director of the Henri and Belinda Termeer Center for Targeted Therapies. Her primary clinical focus is cutaneous oncology. Dr. Boland is also a mentor for the next generation of academic surgeons and research scientists.        

Genevieve M. Boland, MD, PhD, and her colleagues in the Boland Lab at Massachusetts General Hospital lead correlative immuno-oncology efforts in melanoma and gastrointestinal malignancies. The lab’s primary research focus is to utilize patient-derived specimens (tumors/blood) to: 

• Understand cancer biology.
• Identify mechanisms of response and resistance to current therapies.
• Identify biomarkers of therapeutic responses and immune-related toxicities.
• Nominate new targets for combinatorial trials.
  
  Dr. Boland’s recent work supported by Termeer Program funding has focused on integrating sequencing and multi-omics with single-cell resolution imaging done with the Laboratory of Systems Pharmacology. Using these integrated data sets, the team is characterizing tumor-immune interactions, tumor evolution over time, and features of high-risk biology as potential biomarkers to impact therapeutic decision-making. In addition, ongoing work has expanded to focus on melanomas from non-skin sites that are enriched in non-white patients and have poorer responses to therapy.  

Description of Work

Learn More

• From Nature Medicine: “Evolution of delayed resistance to immunotherapy in a melanoma responder” 
  
  
• From Nature: “Targeting TBK1 to overcome resistance to cancer immunotherapy” 
  

INNOVATION

Converging technologies will bring medical breakthroughs. The LSP integrates lab investigation, computer science, and clinical research to develop precision approaches for diagnosing and treating disease.

OPEN SHARING

Open data drives discovery. 
The LSP is committed to accelerating research 
by making its methods, publications, software, and datasets freely available to the broader scientific community.

TRANSLATION

Patients' needs guide the work. 
Partnering with clinicians, the LSP aims to develop and deploy novel, clinic-ready solutions that improve patient care. 

TRAINING

We learn better together. 
The LSP team unites people 
with unique perspectives and expertise to cultivate the next generation of interdisciplinary leaders.

Dr. Jenkins is an HMS assistant professor of medicine at Massachusetts General Hospital. His clinical interests include immunotherapy  and melanoma.        

Immunotherapy Pioneer

Immunotherapy has revolutionized the management of metastatic melanoma and various other cancers, opening up fresh therapeutic possibilities and extending the lives of numerous patients. Regrettably, although immunotherapy proves highly successful for certain individuals, it remains ineffective for others. As a recipient of Termeer Program funding, Russell Jenkins, MD, PhD, made significant progress

toward improving our understanding of the response to immunotherapy drugs called immune checkpoint inhibitors within the tumor microenvironment. His lab has continued its quest to learn which patients will respond to immunotherapy as well as how to effectively treat cancer patients who do not respond to immunotherapy alone. 

Scientists at Harvard Medical School are reinventing the discovery and use of therapeutic drugs at the Laboratory of Systems Pharmacology. Here, researchers use a network-based approach to pharmacology, combining quantitative, multifactorial measurement with diverse computational methods to study signaling pathways and their responses to drugs.​