DF/HCC Members Awarded New or Competitively Renewed Federal Funding

November 7, 2019 


The NIH continues to recognize DF/HCC as a leader in cancer research by awarding several new multi-investigator grants to DF/HCC members.

Recent DF/HCC SPORE Renewals

In late September, NCI’s Division of Cancer Treatment and Diagnosis Translational Research Program published the FY19 SPORE Grantees. A SPORE is a Specialized Program Of Research Excellence and utilizes the P50 funding mechanism from the NCI to “promote collaborative, interdisciplinary, translational cancer multi-project research.” With this announcement, DF/HCC member institutions now hold 4 of the 54 SPOREs spread over 20 US states.

DF/HCC SPORE in Breast Cancer


PI: Eric P. Winer, MD
“The DF/HCC SPORE in Breast Cancer brings together laboratory and clinical investigators with the collective desire to unravel some of the most important translational research challenges in breast cancer..."

Sub-Projects:

  • Administrative Core – PI: Eric P Winer (DFCI)
  • Biostatistics and Computational Biology – PI Meredith Regan (DFCI)
  • Biospecimen and Pathology Core – Deborah Dillon (DFCI)
  • Career Enhancement Program – PI  Judy Garber (DFCI)
  • Developmental Research Program – PI Alan D’Andrea (DFCI)
  • Project 1: Overcoming Breast Cancer Resistance to CDK4/6 Inhibition – PI Peter Sicinski (DFCI)
  • Project 2: Combination Immunotherapy Approachesto Overcome Therapeutic Resistance in HER2-Positive Breast Cancer – PI Ian Krop (DFCI)
  • Project 3: Improving Therapeutic Approaches for Breast Cancer Brain Metastases – PI Nancy Lin (DFCI)
  • Project 4: Combined Use of Immunotherapy and Targeted Treatments for Triple Negative Breast Cancer – PI Kornelia Polyak (DFCI)

Abstract

The Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Breast Cancer seeks to improve the understanding and treatment of breast cancer using an innovative and highly translational approach. The application consists of four projects, three cores, a developmental research program (DRP) and a career enhancement programs (CEP). Each project addresses a fundamental challenge that results in premature mortality or substantial morbidity. Project 1 brings together outstanding investigators to study mechanisms of resistance to CDK4/6 inhibitors. In estrogen receptor-positive breast cancer, we hypothesize that CDK2 hyperactivation is a cause of acquired resistance to CDK4/6 inhibitors. Elegant preclinical work will be complemented by a clinical study in which paired biopsies are obtained prior to initiation of CDK4/6 inhibitors and when resistance develops. In triple-negative breast cancer, we will evaluate the possibility that lysosomal sequestration of CDK4/6 inhibitors limits their therapeutic efficacy. In preclinical work, we will determine if this sequestration can be reversed administering chloroquine and will also conduct a trial of palbociclib/chloroquine in RB-intact triple-negative disease. Project 2 uses two “co-clinical” trials – running randomized human trials and mouse experiments largely in parallel – to study two novel therapeutic approaches to enhance the anti- tumor immune response against HER2-positive breast cancers (CDK4/6 inhibition and dual PDL1 and 4-1BB targeting). Both approaches are based on our compelling preclinical data and will include local and international collaborators. Project 3 tackles the challenge of breast cancer brain metastases. Leveraging our unique collection of xenografts derived from resected human brain metastases, and our experience conducting brain metastasis-specific trials, we will test the biologic and clinical impact of two novel systemic therapy regimens. Project 4 is focused on triple-negative breast cancer. We will perform comprehensive preclinical studies and clinical trials to determine whether targeted therapies can sensitize triple-negative tumors to immunotherapy. We will evaluate combinations of either PARP inhibitors or BET bromodomain inhibitors with immune checkpoint blockade. Core A, the Administrative Core, is the epicenter of scientific, fiscal and administrative oversight. It will lead efforts in planning and communication, and also houses the Patient Advocacy Committee. Core A will ensure that existing DF/HCC structures support the SPORE clinical research efforts. Core B, the Biostatistics and Computational Biology core, provides specialized expertise in biostatistics and management of genomic data. Core C, the Biospecimen and Pathology Core, will maintain tissue/blood repositories for the SPORE projects and for investigators outside of the SPORE. It also provides critical pathology services for the projects and will perform cutting edge assays. Core C also houses the Immuno-Oncology Sub Core. The DRP and CEP identify novel approaches to translational questions in breast cancer and support young investigators. Our SPORE in Breast Cancer is poised to make substantial contributions over the next five years and beyond.

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DF/HCC SPORE in Gastrointestinal Cancer


PIs: Adam Bass, MD, Nabeel El-Bardeesy, PhD
“...in our new SPORE we have developed new projects on development of targeted therapies for gastroesophageal cancers and cholangiocarcinoma thus helping our SPORE to address the diverse set of lethal cancers within the umbrella of gastrointestinal cancers."

SUBPROJECTS

  • Administrative Core – PI Adam Bass (DFCI)
  • Pathology and Biospecimen Core – PI Jason Hornick (BWH)
  • Bioinformatics and Biostatistics Core – PI John Quackenbush (HSPH)
  • Career Enhancement Program – PI Robert Mayer (DFCI)
  • Developmental Project Program – PI Ramesh Shivdasani (DFCI)
  • Project 1 – Integrating Targeted and Immune Therapies for BRAF Mutant Colorectal Cancer – PI Arlene Sharpe (HMS)
  • Project 2 - Exploiting FGF Receptor Signaling Dependence in Liver Cancer Therapy – PI Nabeel El-Bardeesy (MGH)
  • Project 3 - Improving Therapy for DNA-Damage Deficient Pancreatic Adenocarcinoma – PI Brian Wolpin (DFCI)
  • Project 4 - Characterizing and Overcoming Resistance to ERBB2 Directed Therapy in Metastatic Gastric and Esophageal Adenocarcinoma – PI Adam Bass (DFCI)

ABSTRACT:

This is a competitive renewal application for a SPORE in Gastrointestinal (GI) Cancers originating from the GI Malignancies Program of the Dana-Farber/Harvard Cancer Center (DF/HCC). Since its inception in 2007, the SPORE has established a thriving culture of inter-institutional collaboration that has united basic, clinical, and population scientists into a highly productive translational enterprise. The ability to attract and retain researchers from diverse disciplines has fostered fundamental discoveries in cancer biology, innovative translational hypotheses, and cutting-edge clinical trials. The SPORE has also maintained a central focus on developing a large cadre of new investigators, building on a successful model of interdisciplinary, cross- campus cooperation that serves as a nidus for inter-SPORE relationships and other collaborations. Moreover, the SPORE has created invaluable research resources, such as the Tissue, PDX and Organoid Repository and clinical, pathology, and genomics databases that collectively accelerate translational investigation. Each of the current projects has achieved or exceeded its translational goals, providing a foundation for programmatic studies, including independent large-scale collaborative initiatives. Building on this progress, the DF/HCC GI SPORE seeks to continue to translate biological and technological advances into improvements in the prevention and treatment of GI malignancies. The overarching objectives of a renewed SPORE are to: 1) Define optimal genomic and functional strategies, including integration of cell-free (cf)DNA profiling (Projects 1-4), to predict drug responsiveness and improve diagnostics, prognostics, and clinical decisions. 2) Elucidate the interplay between oncogenic mutations, targeted therapy, and anti-tumor immunity to inform cancer biology and improve the outcome of patients with GI cancers (Projects 1,3, 4). 3) Define mechanisms of resistance to novel targeted therapies and hence identify new approaches to overcome resistance and better select the patients most likely to respond to therapy (Projects 1-4). 4) Enhance study of deadly GI cancers that, despite rising incidence, remain under- studied (Project 2, 4). 5) Encourage collaboration and promote academic rigor by providing clinical specimens, fostering core technologies and resources, and hosting regular research meetings and seminars focused on GI cancers. 6) Provide mentorship and training for young GI cancer researchers and recruit leading translational investigators from other fields through Career Enhancement and Developmental Project Awards.

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DF/HCC SPORE in Targeted Therapies for Glioma


PI: Tracy Batchelor, MD, MPH
“Going forward into this renewal funding cycle, we will continue to develop targeted therapies for the adult tumors but will also expand our mission so as to include gliomas of children and young adults."

SUBPROJECTS

  • Administration Core – PI Tracy Batchelor (BWH)
  • Pathology Core – PI Keith Ligon (DFCI)
  • Biostatistics and Computational Biology Core – PI Steven Piantadosi (BWH)
  • Career Enhancement Program – PI Tracy Batchelor (BWH)
  • Developmental Project Program – PI Tracy Batchelor (BWH)
  • Project 1 – Targeted Therapies for Pediatric Low-Grade Astrocytoma – PI Daphne Haas-Kogan (BWH)
  • Project 2 – Targeting  IDH-Mutant Gliomas – PI William Kaelin (DFCI)
  • Project 3 – Targeting CDK4/6 to Modulate Immunogenicity in Gliomas – PI Jean Zhao (DFCI)
  • Project 4 – Targeting the Neuronal Microenvironment in Gliomas – PI Mario Suva (MGH)

Abstract

This is the competing renewal of a SPORE initiative on glioma at Dana-Farber/Harvard Cancer Center. Our objective is to improve the standard of care for children, young adults, and adults with these tumors through the use of targeted therapies. Towards this end, basic scientists from Harvard Medical School and the Broad Institute join with clinical/translational investigators from Boston Children’s Hospital, Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Massachusetts General Hospital. There are four projects: Project One targets pediatric low-grade astrocytomas (PLGAs). Nearly 75% of PLGAs are driven by activating mutations in the BRAF protein kinase. Clinician/scientists Daphne Haas-Kogan, M.D. and Karen Wright, M.D. together with structural biologist Michael Eck, M.D., Ph.D. will develop and test brain-penetrant targeted therapeutics for BRAF-mutant PLGAs. Project Two targets IDH-mutant gliomas which present typically in young adults. IDH-mutant gliomas produce extraordinarily high levels of the ‘oncometabolite’ R-2- hydroxyglutarate (2-HG). However, therapeutic exploitation of the differential 2-HG content between normal and malignant brain tissue has yet to be realized. Neurosurgeon Daniel Cahill, M.D., Ph.D. and cancer biologist William Kaelin, M.D. will address this therapeutic lacuna. Project Three targets adult gliomas. Recent studies by basic scientist Jean Zhao, Ph.D. show that in addition to suppressing cell cycle progression, CDK4/6 antagonists promote anti-tumor immunity and synergistically enhance the response to checkpoint inhibitors. Going forward, Dr. Zhao together with neuro-oncologist Patrick Wen, M.D. will test the hypothesis that brain penetrant CDK4/6 inhibitors can augment immunotherapeutic approaches to GBM. Project Four targets the neuronal microenvironment of adult and pediatric gliomas. Neuro-oncologist and developmental neurobiologist Michelle Monje, M.D., Ph.D. has shown that neurons promote glioma growth through activity- regulated secretion of neuroligin-3 (NLGN3) into the tumor microenvironment. Basic scientist Mario Suva, M.D, Ph.D. has refined methods for single cell sequencing of the multiple cell types within the microenvironment of freshly resected human gliomas. Working together, Monje and Suva will define the molecular mechanisms whereby microenvironmental NLGN3 modulates formation and progression of gliomas and explore a novel therapeutic opportunity embedded within the NLGN3 requirement. Rigor and reproducibility of work conducted in the four projects will be fostered by cores for Pathology and for Biostatistics and Computational Biology. An Administration core will enable and manage the multiple consortium agreements and collaborative interactions between Harvard Medical School, the four participating Harvard teaching hospitals and facilitate clinical trials and imaging studies. Intellectual vigor within the program is sustained and refreshed by annual Career Enhancement Awards to young investigators and by annual Developmental Project Awards.

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DF/HCC SPORE in Multiple Myeloma

PIs: Kenneth Anderson, MD, Nikhil Munshi, MD
“...we will continue our translational studies to develop novel therapies targeting protein homeostasis, characterize and target causes of genomic instability, as well as develop novel targeted therapeutics for Waldenstrom’s Macroglobulinemia."

Sub-Projects:

  • Administration, Communication, and Planning Core – PI Kenneth Anderson
  • Biostatistics and Bioinformatics – PI Giovanni Parmigiani (DFCI)
  • Tissue Banking Core – PI Nikhil Munshi
  • Career Enhancement Program – PI Kenneth Anderson
  • Developmental Research Program – PI Kenneth Anderson
  • Project 1 – Therapeutically Targeting Ubiquitin Receptors in Multiple Myeloma – PI Kenneth Anderson
  • Project 2 – Targeting AP Nuclease, a Mediator of Genomic Instability in Multiple Myeloma – PI Nikhil Munshi
  • Project 3 – Targeting Mutated MYD88 Signaling in Waldenstroms Macroglobulinea – PI Steven Treon (DFCI)

Abstract

The Dana Farber/Harvard Cancer Center (DF/HCC) multiple myeloma (MM) SPORE renewal application consists of 3 Research Projects and 3 Cores, as well as the Career Enhancement and Developmental Research Programs. During the previous funding period, we have capitalized on the complementary strengths of the research, clinical expertise, and facilities of the Harvard affiliated institutions including Dana Farber Cancer Institute, Massachusetts General Hospital, Harvard Medical School, and Harvard School of Public Health. We have successfully translated multiple novel agents from the bench to the bedside and FDA approval for treatment of MM. In this SPORE renewal application one new project has evolved from prior Developmental Projects, and three investigators who are now Co-PI's have previously received Developmental Research or Career Enhancement Awards. This new project focuses on developing novel therapeutic strategies in Waldenstrom's macroglobulinemia, a plasma cell disorder with unique biology. The group as a whole has a long-term commitment to translational MM research, with the necessary administrative, basic science, and clinical infrastructure. At our well established centers, more than 750 new patients with MM are evaluated annually, as well as 10,000 outpatient visits for established patients with plasma cell dyscrasias. The spectrum of diseases evaluated spans from monoclonal gammopathy of unclear significance to plasma cell leukemia to Waldenstrom's macroglobulinemia. Our center has appropriate scientific and institutional review boards, as well as protocol audit and quality control centers, to conduct cutting-edge translational research. This large combined patient base assures rapid accrual and evaluation of the therapeutic efficacy of novel agents identified in this program with over 40 active protocols. Success of both the preclinical and clinical components of this Program is dependent upon synergy and communication between these investigators which is assured by the access to all the Principal Investigators to the preclinical data generated in joint research efforts. Currently there is systematic quality-controlled exchange of bone marrow and blood samples for correlative basic laboratory studies. The overall goal of this DF/HCC myeloma SPORE is to take advantage of our increased understanding of the genetic and molecular basis of multiple myeloma and Waldenstrom's macroglobulinemia to develop novel, effective therapeutic strategies for patients. The translational nature of the SPORE is highlighted by the fact that most of our projects have emanated from clinical studies from the outset. Specific Projects are: (1) Therapeutically Targeting Ubiquitin Receptors in Multiple Myeloma; (2) Targeting AP Nuclease, a Mediator of Genomic Instability in MM; (3) Targeting Mutated MYD88 Signaling in WM; An Administration Communication and Planning Core; as well as Tissue Core 1 and Biostatistics and Bioinformatics Core 2, will continue to support the program. This Program therefore helps move rational novel targeted therapies from the laboratory to clinical protocols to improve patient outcome in MM.

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Other Featured NIH Funding

 

Predicting Fracture Risk in Patients Treated with Radiotherapy for Spinal Metastatic Disease

NIAMS - 1R56AR075964-01
PIs: Ron Alkalay (Harvard University), Tracy Balboni (DFCI), David Hackney (Beth Israel Deaconess Medical Center)
Patients treated with radiation therapy for metastatic disease of the spine suffer high risk for pathologic spinal fractures (PVF) an integral part of spinal adverse events (SAE). In this work we will determine whether a prediction model, based on our computed tomography (CT) based assessment of structural analysis protocol (SAP) and the measurement of blood turnover markers, demonstrates significantly higher performance in predicting the risk of PVF compared to current clinical protocols in this patient cohort. This study will provide novel data for establishing quantitative assessment of PVF risk in patients with spinal metastasis, thus addressing a critical gap in the ability to evaluate and treat these patients.

Advancing Palliative Care in Northern Plains American Indians

NCI - 1R01CA240080-01
PIs:Katrina Armstrong (MGH), Daniel Petereit (Regional Health John T. Vucurevich Cancer Care Institute)
American Indians in the Northern Plains experience high rates of cancer mortality, inadequate access to cancer care, and adverse social conditions, making the development of an innovative and culturally appropriate model of palliative care delivery a priority for tribes, providers and health care systems in Western South Dakota. In this application, we propose a two-phase study that will develop and evaluate a novel, culturally appropriate approach to the delivery of palliative care services that builds upon existing work in the Northern Plains and advances in palliative delivery in other settings. This proposal leverages a collaboration across 8 organizations committed to improving the health of American Indians in Western South Dakota, an extraordinary opportunity to address a key aspect of the quality of cancer care in one of the most underserved rural populations in the US.

Oncolytic virus therapeutic responses occur from changes in the glioblastoma immune microenvironment

NINDS - 1R01NS110942-01A1
PIs: Antonio Chiocca (BWH), Hiroshi Nakashima (Brigham and Women's Hospital)
Glioblastoma (GBM) is a fatal brain cancer without cures. We have been using an oncolytic virus to increase the response of anticancer immune cells against GBM. We show in mice models that antiGBM responses depend on increasing the number of anticancer T cells against GBM and want to determine how to improve these numbers. If successful, these studies will show how the immune system can be instructed to destroy GBM cells.

The Implementation Science Center for Cancer Control Equity

NCI - 1P50CA244433-01
PIs: Karen Emmons (HSPH), Elsie M. Taveras (MGH)
The Implementation Science Center for Cancer Control Equity (ISCCCE) focuses on improving community health by addressing health equity in implementation science for cancer control in studies conducted in community health centers and the communities that they serve.

Lymph Node Quantification System for Multisite Clinical Trials

NCI - 1R01CA235589-01A1
PIs: Ron Kikinis (BWH), Gordon Harris (MGH)
Advanced quantitative imaging is underutilized in oncologic clinical practice and research because the time investment entailed in manual lesion segmentation remains prohibitive. This partnership proposes to integrate machine learning based quantitative imaging tools into the existing Precision Imaging Metrics, LLC clinical trial image management system. We will use data from the centralized Tumor Imaging Metrics Core at the Dana- Farber/Harvard Cancer Center to produce ground truth training data and develop semi-automated multimodali- ty lesion analysis for patients with cancer.

Fluorinated macrocyclic peptides as BBB penetrating agent for improved GBM treatment

NCI - 1R01CA237063-01A1
PIs: Sean Lawler (BWH), Bradley Lether Pentelute (Massachusetts Institute of Technology)
The blood-brain barrier (BBB) is a specialized cellular structure that closely regulates the entry of drugs and biological molecules into the brain and represents a severe challenge to treating diseases of the brain, as potentially beneficial medicines often cannot reach their targets inside the CNS. This is a major obstacle for the treatment of brain tumors which may not be exposed to drugs which could otherwise destroy them. Here, we propose to develop agents engineered to cross the BBB and deliver brain tumor killing drugs.

Systems Biology of Bone Marrow Failure and MDS for Precision Medicine

NIDDK - 1RC2DK122533-01
PIs: Akiko Shimamura (DFCI), Maria Eugenia Figueroa (University of Miami), Mark D Fleming (Boston Children's Hospital), Robert Coleman Lindsley (DFCI)
Bone marrow failure (BMF) leads to low blood cell counts and can be associated with myelodysplastic syndrome (MDS), a pre-leukemic condition. Knowing the specific genetic causes of BMF and the changes associated with progression to leukemia allows physicians to treat or prevent life-threatening medical conditions of BMF/MDS. This grant seeks to expand our understanding of the genes that cause BMF/MDS as well as the acquired changes that occur during progression to leukemia using state-of-the-art gene sequencing and other cutting-edge molecular technologies to inform personally tailored medical management.

Defining mechanisms of immunotherapy resistance in head and neck squamous cell carcinomas

NIDCR - 1U01DE029188-01
PIs: Ravindra Uppaluri (DFCI), David Barbie (DFCI), Robert Haddad (DFCI)
Tumor cell intrinsic resistance is a major barrier preventing many head and neck squamous cell carcinoma (HNSCC) patients from benefiting from FDA-approved anti-PD1 immunotherapeutics. Our supporting data in HNSCC preclinical models affirm the existence of diverse intrinsic immunotherapy resistance mechanisms, some of which are likely specific to HNSCC. Herein, we propose integrated functional and correlative studies of high fidelity preclinical models and patient tumors to define intrinsic resistance barriers to HNSCC immunotherapy and to delineate new therapeutic approaches.

Harvard Education Program in Cancer Prevention Control

NCI - 2T32CA057711-26
PIs: Kirsten Davison (Harvard TH Chan School of Public Health), Karen Emmons (HSPH)
This training program is in its 24th year, and has trained 116 fellows in transdisciplinary approaches to cancer prevention and control. Eighty-eight percent of trainees currently hold a research-focused position. The maturity of this Program, extensive resources available through Harvard and synergy across the focal training areas provide an outstanding platform for training the next generation of cancer prevention scientists. 

Information Processing by Post-translational Modification

NIGMS – 2R01GM105375-05
PIs: Jeremy Gunawardena (Harvard Medical School), Neil Kelleher (Northwestern University), Galit Lahav (HMS)
Most proteins in an organism are chemically modified on a reversible basis and disruptions to such “post-translational modification” (PTM) play an important role in diseases like cancer and Alzheimer's. In this multi-disciplinary proposal, we build upon previous experimental, mathematical and computational advances to analyze the tumor suppressor and “guardian of the genome” p53, which is modified at over 100 sites. We expect to learn a great deal about how p53 processes information as a central cellular hub, while developing concepts and methods which can be widely applied to other proteins in which PTM plays a key role.

Workshop on Methods in Supportive Oncology Research

NCI - 2R25CA181000-06
PIs: William Pirl (DFCI), Jennifer Temel (MGH)
Cancer continues to cause suffering, both physically and psychologically. While supportive oncology research has potential to alleviate this suffering, more research and trained investigators are needed. We propose to continue a successful intensive training program on supportive oncology research methods to meet this need.