Research Center

Center for Cancer Systems Pharmacology (CCSP)

Overview

Center Title

Center for Cancer Systems Pharmacology (CCSP)

Center Website

TBA

Center Summary

The Center for Cancer Systems Pharmacology (CCSP) based at Harvard Medical School focuses on constructing and validating network-level models of responsiveness and resistance (innate and acquired) to immune checkpoint inhibitor (ICI) and small molecule (targeted) therapies in human cancer. The over-arching goal is to improve the treatment of disease and advance molecular understanding of oncogenic transformation and opposing immune surveillance on the initiation and progression of human cancer. Our Center also studies the adverse effects of targeted therapies, with an initial focus on ICI toxicity in the skin.
Our approach involves the use of systems pharmacology tools and concepts to address the most significant questions encountered in the use of ICIs and targeted therapies individually and in combination in melanoma, in which both classes of drug can be highly effective individually, and also in triple negative breast cancer (TNBC) and glioblastoma multiforme (GBM) in which clinical responses are sporadic. In the long-term, expected outcomes include (i) translating clinical problems in melanoma, TNBC and GBM from the bedside to bench and then back to the bedside via new drug-disease pairings, drug combinations and response biomarkers (ii) developing, validating and applying to clinical trials innovative pharmacological concepts that consider the impact of cell-to-cell variability, micro environment, and dose and drug sequencing on outcomes and (iii) reducing the burden of therapy through improved understanding of mechanism-based drug toxicities and ways of mitigating them.

Conceptual focus of the CCSP Center. We study mechanisms of therapeutic and adverse response and of drug resistance in melanoma, in which both ICIs and targeted therapy are effective, and triple negative breast cancer (TNBC) and brain cancers, in which they are sporadic and a significant unmet need exists. (+) signs denote responsiveness to therapy.

Investigators

Principal Investigators

Peter Sorger (PI)

Peter Sorger (PI), Otto Krayer Professor of Systems Biology; Founding Director of the Laboratory of Systems Pharmacology and Head of the Harvard Program in Therapeutic Science in which the Center for Cancer Systems Pharmacology (CCSP) is based. Dr. Sorger’s research focuses on the systems biology of mammalian signal transduction and the drugs that target oncogenic signaling proteins. His group uses single-cell and multiplexed imaging and mass spectrometry methods to constrain and validate physico-chemical models of oncogenesis and drug action.

Sameer Chopra

Sameer Chopra, Instructor of Medicine, Harvard Medical School (HMS); Attending Physician, Dana-Farber Cancer Institute (DFCI); Research Associate, Harvard Program in Therapeutic Science. Dr. Chopra studies mechanisms of immune evasion in women’s cancers (breast, ovarian, endometrial) and their relationship to specific molecular and phenotypic aberrations commonly found in these tumors such as replication stress and genome instability. He aims to improve strategies for initiating and sustaining effective anti-tumor immune responses in patients using rational combinations of small molecule drugs, immunotherapy, and chemotherapy.

Conor Evans

Conor Evans, Assistant Professor at the Wellman Center for Photomedicine of Harvard Medical School at the Massachusetts General Hospital. Dr. Evans develops advanced imaging technologies for the direct visualization and quantification of pharmacokinetics and pharmacodynamics in situ. By leveraging tools such as coherent Raman imaging, image analysis, and machine learning, his group aims to improve our understanding of how cancer drugs reach and engage their targets.

Keith Flaherty

Keith Flaherty, Director of the Termeer Center for Targeted Therapies, Director of Clinical Research at the Massachusetts General Hospital; Professor of Medicine at Harvard Medical School. Dr. Flaherty focuses on understanding mechanisms of action and resistance to signal transduction targeted therapy and immunotherapy in melanoma, as well as the mechanistic interaction between the two modalities. Deep molecular analysis of serial tumor biopsies and rapid autopsy samples are used to motivate functional pre-clinical studies and to inform next generation clinical trials.

Jennifer Guerriero

Jennifer Guerriero, Director of the Breast Immunology Laboratory in the Women’s Cancer Program at Dana-Farber Cancer Institute; Instructor in Medicine at Harvard Medical School. Dr. Guerriero studies the role of tumor associated macrophages (TAMs) in promoting tumorigenesis and as a therapeutic target. Her research aims to understand the molecular and functional regulation of tumor macrophage phenotype and subsets, identify how tumor macrophages inhibit T cell function and limit the effectiveness of immunotherapy, and identify novel strategies to target macrophages therapeutically.

Marcia Haigis

Marcia Haigis, Associate Professor in the Department of Cell Biology at Harvard Medical School. Dr. Haigis studies the metabolic programs of mammalian cells and the pathways that regulate these programs. She focuses on metabolic reprogramming of tumor cells and immune cells within the tumor microenvironment to discover novel anti-tumor therapies.

Steve Hodi

Steve Hodi, Director of the Melanoma Center and the Center for Immuno-Oncology, and Institute Physician at the Dana Farber Cancer Institute; Sharon Crowley Martin Chair in Melanoma; Professor of Medicine at Harvard Medical School. Dr. Hodi studies mechanisms of immuno-therapy via clinical trials in multiple disease areas. He focuses on understanding determinants of response and the specific disease features that allow a subset of patients to experience extremely durable responses to immune checkpoint inhibition.

Benjamin Izar

Benjamin Izar, Medical Oncologist in the Department of Medical Oncology (Melanoma Disease Center) and Center for Immunology and Virology at the Dana-Farber Cancer Institute; Center for Cancer Precision Medicine at the Dana-Farber Cancer Institute; investigator at the Broad Institute of MIT and Harvard. Dr. Izar has pioneered the implementation of single-cell RNA-sequencing and single-cell protein imaging in clinical specimens and the development of patient-derived models to understand drug resistance to targeted therapies and immune checkpoint inhibitors. As a medical oncologist, he focuses on the treatment and understanding of drug resistance in melanoma.

Darrell Irvine

Darrell Irvine, Professor in the Departments of Biological Engineering and Materials Science & Engineering, Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, Ragon Institute of MGH, MIT, and Harvard; Howard Hughes Medical Institute Investigator. Dr. Irvine’s laboratory is focused on the development of combination immunotherapies leveraging innate and adaptive immune pathways as a means to eradicate established tumors. His group is particularly interested in combination therapies that trigger an “in situ” vaccination response.

Douglas Lauffenburger

Douglas Lauffenburger, Ford Professor of Biological Engineering, Chemical Engineering, and Biology Head, Department of Biological Engineering at the Massachusetts Institute of Technology. Dr. Lauffenburger studies cell dysregulation in complex pathophysiologies, emphasizing applications in cancer, inflammatory diseases, and vaccines. A central objective is gaining understanding of how multiple pathways and processes — both intracellular and intercellular – combine to govern cell functions and how they become dysregulated in disease.

Nicole Leboeuf

Nicole Leboeuf, Director, Center for Cutaneous Oncology at Dana-Farber/Brigham and Women’s Cancer Center, Director of Dermatologic Immunology; Clinic Director of Skin Toxicities from Anticancer Therapies Clinic; Assistant Professor at Harvard Medical School. Dr. Leboeuf provides urgent and ongoing expert dermatologic care for cancer patients with cutaneous adverse events from oncologic treatments. Her research focuses on profiling the immune infiltrate in the skin and blood of patients with cutaneous eruptions from immune checkpoint blockade.

Patrick Ott

Patrick Ott, Attending Physician in the Department of Medicine at Brigham and Women’s Hospital; Clinical Director of the Center for Immuno-Oncology and Melanoma Center at the Dana Farber Cancer Institute; and Assistant Professor at Harvard Medical School. Dr. Ott is interested in the development of new immunotherapeutic strategies for cancer patients. He is the principal investigator and site investigator of a large portfolio of clinical trials assessing novel agents and innovative combinatorial strategies for patients with melanoma and other cancers.

Sandro Santagata

Sandro Santagata, Associate Pathologist in Neuropathology at the Brigham and Women’s Hospital and the Dana Farber Cancer Institute; Assistant Professor in Pathology at Harvard Medical School. Dr. Santagata is interested in applying novel imaging methods, including tissue-based cyclic immunofluorescence (t-CyCIF) to brain tumor resection specimens from clinical trials in order to measure and model responses in tumors and their microenvironment before and after therapy.

Arlene Sharpe

Arlene Sharpe, George Fabyan Professor of Comparative Pathology, Head of the Division of Immunology; Co-Director of the Evergrande Center for Immunologic Diseases; Chair of the Department of Immunobiology at Harvard Medical School. Dr. Sharpe studies T-cell costimulation and its immunoregulatory functions in T cell tolerance and anti-tumor immunity. Her laboratory has been at the forefront of this field for over two decades, discovering T cell costimulatory pathways, and elucidated their functions, including the functions of B7-1 and B7-2, CTLA-4, ICOS, PD-1 and PD-1 ligands.

Projects

Project 1: Multi-scale modeling of adaptive drug resistance in BRAF-mutant melanoma

We are constructing families of computational models, at different levels of molecular detail, that capture and ultimately explain the diversity of phenomena associated with resistance to RAF/MEK inhibitors. This is accomplished by collecting time-series single-cell and population-level data from cells with diverse genotypes followed by time-resolved modeling using differential equations, logic-based models and supervised machine learning. These studies are performed initially in patient-derived cell lines and mouse models, but intended to provide hypotheses that can be tested in clinical trials.

Project 2: Measuring and modeling the tumor and immune microenvironment before and during therapy and at the time of drug resistance

We study changes in the tumor ecosystem induced by ICIs or targeted therapy and predictive of therapeutic response. The precise proportions and spatiotemporal arrangements of tumor, stromal and immune cells will be determined in tissue biopsies, and single-cell features will be extracted and associated with disease progression and therapeutic response using machine learning, deep learning and high-dimensional data analysis. Adverse responses in the skin and gut will also be investigated and compared to therapeutic responses at a mechanistic and clinical level.

Project 3: Mechanisms of immunotherapy action

We study ICIs alone or in combination in tumor-bearing mice to evaluate whether highly efficacious responses arise from co-targeting cells of single lineages (e.g. CD8+ effector T cells) or concurrent targeting of multiple cell lineages (e.g. CD8+ T cells, regulatory T cells), and to identify the tumor settings in which either strategy might prove more effective. Metabolic, signaling, and transcriptional changes associated with cellular responses to ICIs are assessed and modeled. Agent-based models are then used to study non-cell autonomous mechanisms that mediate therapeutic and adverse drug effects. We hope to thereby discover combinations of ICIs and specific patient populations in which therapeutic responses are high and toxicity is minimal.

Cores

Systems Pharmacology Core

The Systems Pharmacology Core provides all CCSP members, as well as individuals selected for funded internal research projects, access to a central, high quality resource for molecular profiling of cells and tissues and for data analysis. The core will join together four approaches based in the Laboratory of Systems Pharmacology (LSP) (i) deep, high throughput, and single cell RNA-Seq (ii) targeted and shotgun mass-spectrometry based proteomics (iii) high dimensional single cell imaging and (iv) data analysis and data science based on supervised and unsupervised machine learning as well as two technologies based in the laboratories of CCSP investigators (i) metabolomics profiling (via Haigis lab) and (ii) immune profiling of blood using flow cytometry and multiplex cytokine assays (via the DFCI Immune Profiling Lab). These activities do not take place in isolation, and all of our platform technologies work closely with HMS core facilities in a hub and spoke model..