DF/HCC Members Awarded New or Competitively Renewed Federal Funding

December, 2017 

The NIH continues to recognize DF/HCC as a leader in cancer research by awarding funding to a number of our research initiatives. Recently, this funding included the following new grants:

System Analysis of Cell Type Differentiation in Xenopus Development
NCI - 2R01HD073104-06 - Research Project 
PIs: Marc Kirschner (HMS), Leon Peshkin (HMS)

The complexity of biology makes it hard to predict what effect a mutation or a drug will have. We will use new tools to measure when genes are expressed at the individual cell level throughout the course of development of a vertebrate embryo. This will give us new information on the cell types involved in tissue and organ formation, and will provide an unprecedentedly detailed dataset that we will use to develop a mathematical model of how the decision to become a specific cell type is made.

An Integrated Translational Approach to Overcome Drug Resistance 
NCI - 1U54CA224068-01 - Specialized Center- Cooperative Agreements
PIs: Ryan Corcoran (MGH), Kieth Flaherty (MGH)

Drug resistance represents one of the most critical obstacles to clinical benefit for cancer patients. We propose a collaborative team of experts from three leading institutions to define key mechanisms of bypass resistance over three tumor types—lung, melanoma, and GI cancer—involving three of the most important classes of anticancer agents—MAPK pathway inhibitors, Receptor Tyrosine Kinase inhibitors, and Immune Checkpoint inhibitors. We expect that this project will lead to a steady stream of novel clinical trial strategies with the potential for transformative impact on cancer patients.

Integrated Model of Palliative and Primary Care in Seriously Ill Older Adults 
NIA - 1R56AG055728-01 - Research Project 
PI: Ziad Obermeyer (BWH), Jennifer Temel (HMS)

Despite major advances in palliative care for patients with specific diseases, we know little about how to deliver palliative interventions `upstream'—earlier in the disease trajectory for older adults with multiple chronic conditions. We will apply advanced predictive modeling techniques (`machine learning') to identify older patients in a primary care setting who would benefit most from palliative care: those whose complex interplay of chronic conditions puts them at high risk of near-term death. Building on our team's strong infrastructure for clinical trials in palliative care, we will enroll the highest-risk patients in a randomized controlled trial, comparing usual primary care to primary care integrated with palliative care..

A Prospective, Multi-Center Pivotal Study of the LUM Imaging System for Real-Time, In Vivo Margin Assessment in Breast Conserving Surgery 
NCI - 1R01CA212138-01 - Research Project
PIs: Barbara Smith (MGH), Anees Chagpar (Yale), Jorge Ferrer (California Institute of Integral Studies), Kelly Hunt (MD Anderson), Eun-Sil Hwang (Duke), Irene Wapnir (Stanford)

The proposed project aims to address the unmet clinical need for intraoperative assessment and removal of residual cancer cells in the lumpectomy cavity after gross tumor resection in breast cancer patients. A novel imaging method for fast and thorough imaging of the tumor bed in real-time will be tested in a pivotal clinical study to measure efficacy in reducing positive margin rates and eliminating the need for repeat surgeries. Successful completion of this project will enable the FDA approval required to put this technology in the hands of breast cancer surgeons, improving care for breast cancer patients.

Cancer Epidemiology Cohort in Male Health Professionals 
NCI - 2U01CA167552-06 - Research Project – Cooperative Agreements
PIs: Walter Willett (HSPH), Lorelei Mucci (HSPH)

This project will support the core infrastructure and follow-up of the Health Professionals Follow-up Study (HPFS), a cancer epidemiology cohort of 51,529 male health professionals followed for three decades since 1986. The cohort includes biennial questionnaires and prospectively collected biospecimens including: plasma, red cells, germline DNA, toenail samples, and tumor tissue. With additional follow-up of the cohort, particularly after cancer diagnosis, the cohort remains ideally positioned to make innovative contributions to the overall goal of reducing the burden of cancer and identifying primary and secondary prevention strategies.

Image-guided Drug Delivery for Pancreatic Neuroendocrine Tumor 
NIBIB - 1R01EB022230-01A1 – Research Project
PIs: Hak Soo Choi (BIDMC), Maged Henary (Georgia State)

Pancreatic neuroendocrine tumors cannot be adequately treated using conventional treatments and remain an unanswered health concern. Diagnosis of these cancers is often difficult due to the small size of the tumors, and the lack of specific symptoms and biomarkers for reliable early detection. Targeted multifunctional nanoprobes can provide sensitive and specific imaging of pancreatic neuroendocrine tumors for early diagnosis, site-specific delivery of chemotherapeutic agents, and laparoscopic image-guided surgery.

SPORE in Myeloid Malignancies 
NCI - 1P50CA206963-01A1
 - Specialized Center
PIs: Benjamin Ebert (DFCI), Richard Stone (DFCI)

Myeloid malignancies are cancers that are caused by overgrowth of bone marrow stem cells, leading to abnormal production of blood cells. Understanding the mechanisms that allow such overgrowth will provide an avenue to develop therapeutic strategies that specifically inhibiting the abnormal pathways and/or aid the patient's own immune system to recognize these abnormal cells. Research in the SPORE will develop new therapies that could be more specifically effective than current cytotoxic drugs.

Reprogramming PDAC Tumor Microenvironment to Improve Immunotherapy 
NCI - 1U01CA224348-01 - Research Project – Cooperative Agreements
PIs: Rakesh Jain (MGH), Mikael Pittet (MGH)

The goal of this U01 and the future collaborations with the PDAC Consortium is to provide novel mechanistic insights into reprogramming the immunosuppressive tumor microenvironment of PDAC into an immunostimulatory one. Our approach to achieve this will be to use widely prescribed and inexpensive inhibitors of the angiotensin II signaling. Our preliminary data show that angiotensin II signaling mediates not only the desmoplastic reaction characteristic of PDACs, but also immunosuppression via effects on innate and adaptive immunity. The resulting data will directly inform the design of a clinical trial to test the efficacy of combining losartan—an angiotensin II signaling inhibitor—and cytotoxic agents with immune checkpoint blockers in a multi-institutional trial led by our clinical collaborators at the MGH Cancer Center. By altering the tumor microenvironment in this manner, we aim to overcome resistance to standard and emerging systemic therapies for this intractable disease.

Engineering Personalized Micro-Tumor Ecosystems 
 NCI - 1U01CA214411-01A1 – Research Project – Cooperative Agreements
PIs: Ali Khademhosseini (BWH), Shiladitya Sengupta (BWH)

Despite the recent development of subtype-specific personalized therapy based on achievements in the fields of molecular and genetic profiling, the cancer treatment still has low efficacy that mostly arise from the limited ability of existing models to recapitulate the tumor heterogeneity and therefore predict the patient tumor responses to therapeutic agents. We propose to develop a novel personalized breast-cancer-ecosystem platform for personalized screening of cancer chemotherapeutics with extremely high accuracy by utilizing patient-derived tumor explant culture, defined tumor grade-matched biomaterial matrices, and autologous patient serum to mimic patient-specific tumor hallmarks. The integration of a machine-learning algorithm will further provide precise and unbiased prediction of the patient responses to chemotherapeutics based on the data gathered from the engineered tumor ecosystem.

Single-Cell Analysis of Tumor-Microenvironment Interactions in Follicular Lymphoma 
NCI - 1R21CA220147-01 – Exploratory/Developmental Research Grant
PIs: Peter Kharchenko (HMS), Catherine Ju-Ying Wu (DFCI)

Follicular Lymphoma (FL) is a cancer of the lymphatic system, which despite its slow growth remains incurable with the current therapies. Many of the FL patients quickly develop resistance to therapy or a more aggressive form of a disease, such progression appears to be linked to the presence of other, non-malignant cells in the FL tumors. Using novel measurement techniques, we will examine the detailed composition of the FL tumors at single-cell level, aiming to identify molecular signatures associated the patient’s response to treatment, and suggest potential avenues for disrupting detrimental tumor-microenvironment interactions.

Cancer Immunologic Data Commons 
NCI - 1U24CA224316-01 – Resource-Related Research Projects – Cooperative Agreements
PIs: Xiaole Liu (DFCI), Ethan Cerami (DFCI)

Establishing biomarkers of drug response and resistance is of utmost importance to cancer immunotherapy in order to improve overall efficacy, minimize side effects, and reduce costs. The current network of NCI- supported clinical trials lacks standardization in data acquisition and processing, and require significant data integration and bioinformatics efforts. Our work will build the infrastructure for a centralized biomarker data repository and state-of-the-art informatics tools.

Precision Assessment and Delivery of Cancer Risks in BRCA 1/2 Mutation Cancers  
NCI - 1R01CA207365-01A1 – Research Project
PIs: Timothy Rebbeck (DFCI), Jinbo Chen (UPenn)

In current risk assessment and counseling practices, all women who test positive for a deleterious BRCA1/2 mutation are quoted the same general range of ovarian cancer risk and are given the same recommendation regarding utilization of risk reducing salpingo- oophorectomy (RRSO) and other preventive measures. The results of this proposal will provide precision information about cancer risks to aid women with BRCA1/2 mutations in health decision making. This information will allow women to maintain fertility and minimize the risks of early surgical menopause while obtaining maximum cancer risk reduction.

Cancer Immune Monitoring and Analysis Center 
NCI - 1U24CA224331-01 – Resource-Related Research Projects – Cooperative Agreements
PIs: Catherine Ju-Ying Wu (DFCI), Frank Stephen Hodi (DFCI)

There has been recent rapid expansion of immunotherapy clinical trials to treat patients with cancer as well as of types of sophisticated tests that can be applied to patient blood and tissues collected as part of these clinical trials that promise to provide deep insights regarding why these treatments are effective. The goal of this application is to develop a specialized center with expertise in the important area of new clinical trials and in how we can learn from these trials based on the application of a battery of molecular, pathology and immunologic assays to these samples. We leverage long track record of experience in this area, having performed these types of analyses for our local studies, to now contribute to the creation of a network of similarly-oriented centers to support, harmonize, compare, and disseminate existing and new approaches for learning of the mechanisms underlying responses to immune-based therapies for the treatment of cancer.

Next-Generation Drosphila Cell Lines to Elucidate the Cellular Basis of Human Disease   
NIH - 1R24OD019847-01A1 – Resource-Related Research Projects
PIs: Norbert Perrimon (HMS), Amanda Simcox (Ohio State)

We will generate a resource of Drosophila cell lines, markers, and knockouts that will enable cell biological analysis of genes and pathways altered in human diseases, including in disease-relevant tissue lineages and genetic backgrounds. In recent years, we have witnessed renewed interest in Drosophila cell lines and it is now common for Drosophila researchers to go back and forth between in vivo and cell culture studies. However, the full potential of Drosophila cell lines, particularly for disease-related studies, has not yet been realized, as the diversity of cell lines and markers available is limited. To overcome this bottleneck, we propose to use exciting new advances in cell line immortalization and genome engineering to generate reagents that will enable the community to fully exploit the power of Drosophila cell lines to address disease-related cell biological questions.