DF/HCC Members Awarded New or Competitively Renewed Federal Funding

October 17, 2018 

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

Identification of Genomic Drivers of Brain Metastases in Renal Cell Carcinoma 
NCI - 1R21CA220253-01A1
PIs: Priscilla Kaliopi Brastianos (MGH), Scott Carter (DFCI), Toni K Choueiri (DFCI)

In this study, we propose to identify potential drivers and therapeutic targets of newly diagnosed and recurrent brain metastases from renal cell cancer. Our application is relevant to the public health because there are no effective systemic therapies for patients with brain metastases from renal cell carcinoma. Relevant to the NIH mission, the overarching objective of this study is to identify genetic changes that are associated with more aggressive phenotypes of renal cell carcinoma, with the goal to identify optimal therapeutic approaches for this common neoplasm.

Promoting Follow-up of Abnormal Cancer Screening Tests Using Population-Based Systems to Support Stepped Care Multilevel Intervention 
NCI - 1U01CA225451-01
PIs: Jennifer S Haas (BWH), Steven J Atlas (MGH), Anna N A Tosteson (UC-Davis)

Effective cancer screening requires appropriate diagnostic testing after an abnormal screening result. Timely follow-up of such abnormalities can be challenging due to the complex interactions among patients, primary care providers (PCPs) and specialists. We propose to develop, implement, evaluate and disseminate a health information technology (IT)-enabled, multilevel, stepped care intervention grounded in primary care, mFOCUS (multilevel FOllowup of Cancer Screening) to improve the follow-up of abnormal breast, cervical, colorectal and lung cancer screening results. The study is designed to evaluate the effectiveness of system, team and individual components of mFOCUS vs. standard care by conducting a 4-arm cluster randomized controlled trial (RCT) of 6,400 individuals, at 40 participating practice sites affiliated with three primary care networks, who are due for follow-up of an abnormal cancer screening test.

Single Cell Genome-Wide Myeloid Response Profiling In Immunotherapy
NCI - 1R01CA218579-01A1 
PIs: Allon Moshe Klein (HMS), Mikael J Pittet (MGH)

This grant applies a new, powerful method to profile the states of all immune cells in lung adenocarcinomas. We will use this approach to determine all tumor-infiltrating myeloid (TIM) cell states in humans and their correlation with clinical parameters. By profiling TIMs in mouse models, we will further determine the properties of TIMs that can be justifiably studied in mice, and then dissect the relevance and mechanisms of action of two TIM subsets and three signaling pathways that we have found to be specific to TIMs. 

Early Detection Through Novel Ocean Technology - Ovarian Cancer Exosomal Analysis with Nanoplasmonics 
NCI - 1U01CA233360-01 
PIs: Hakho Lee (MGH), Cesar M Castro (MGH), Daniela M Dinulescu (BWH), Johan Skog (Exosome Diagnostics)

We propose to translate a novel liquid biopsy platform for early cancer detection. Specifically, we will advance a forward-thinking nano-plasmonic platform for comprehensive, high-throughput molecular analyses of extracellular vesicles (EVs). As a targeted cancer application of the platform, we will rigorously address EVs' clinical utility for early detection of ovarian cancer.

Pre-Cancer Atlases of Cutaneous and Hematologic Origin (Patch Center) 
NCI -1U2CCA233262-01
PIs: Peter Karl Sorger (HMS), Jon Aster (BWH), Sandro Santagata (BWH)

Construction of Pre-Cancer Atlases comprising detailed spatial and molecular data on cell state and omic data in melanoma and clonal hematopoiesis will join together the two primary means of diagnosing human cancer: histology and genetics. The atlases we construct will help to identify patients with pre-cancer skin lesions and blood conditions at risk of progressing to malignancy at a sufficiently early stage that aggressive disease can be prevented.

Rewiring of Regulatory Networks in Breast Cancer by Transcription Factor Isoforms 
NCI -1U01CA232161-01 
PIs: Marc Vidal (DFCI)Martha L Bulyk (BWH)

One of the ultimate goals of cancer systems biology is to generate predictive and dynamic models of tumorigenesis by identifying and quantifying all perturbed functional interactions in a cancerous cellular system. Although genome alterations such as amplification, deletion, translocations and mutations, are often considered primary events of cancer progression, cancer-specific alternative isoforms resulting from alternative splicing, alternative sites of transcriptional initiation, and/or alternative transcriptional termination sites, have also been shown to have functional impact on tumorigenesis. In this project, we propose to characterize and model the effect of large numbers of breast cancer-specific transcription factor isoforms on gene regulatory networks (GRNs), with the long-term aim of identifying novel cancer drivers and suppressors, generating mechanistic models of GRN rewiring in cancer, and providing a framework for the design of novel therapeutics. 

Integrating Diet, Lifestyle and Tumor Tissue Molecular Subtyping to Study the Role of Adolescent Calcium Intake on the Risk of Early Onset Colorectal Neoplasia 
NCI - 1R21CA230873-01 
PIs: Kana Wu (HSPH), Shuji Ogino (DFCI)

Our hypothesis is informed by physiology, i.e., that the up to 4-fold increase in IGF1 levels and the physiologic (non-obesity related) insulin resistance at puberty and the higher requirement for calcium renders adolescents particularly susceptible to low calcium intake. In particular, we hypothesize that low calcium intake may be especially harmful among obese or physically inactive adolescents, who in addition to physiological increases, are exposed to even higher insulin and IGF1 levels than normal weight or physically active adolescents. Two out of ten colorectal cancers now occur in people less than age 55. This proposal will provide the groundwork for future molecular studies to elucidate pathways underlying early-onset colorectal neoplasia.

Training in Oncology Population Sciences (TOPS)
NCI - 2T32CA092203-16 
PIs: Deborah Schrag (DFCI), Nancy Keating (BWH)

Research investigation in population science is essential to ensure that discoveries from molecular medicine and clinical trials translate to routine practice and ultimately decrease the population-level burden of cancer. The Dana-Farber Harvard Cancer Center's (DF/HCC) T32 Training in Oncology Population Sciences (TOPS) program will equip postdoctoral fellows with the skills necessary to evaluate cancer care quality and effectiveness, and to develop, test and implement interventions to improve care delivery thereby ensuring that T1/T2 discoveries translate across the T3/T4 bridge to achieve maximal impact on population health. Postdoctoral fellows will pursue a two-year program of mentored research, coursework and professional skills training that supports innovation and leverages the expertise of DF/HCC faculty to prepare them for independent investigation in cancer-focused population science.

Life Course Cancer Epidemiology Cohort in Women 
NCI - 2U01CA176726-06 
PIs: Walter C Willett (HSPH), A Heather Eliassen (BWH)

We propose to continue the follow-up of the Nurses' Health Study II (NHSII), a Cancer Epidemiology Cohort of 116,430 women enrolled in 1989 at ages 25 to 42 years. Data include repeated measures of diet, physical activity, and other exposures over 28 years of follow-up, as well as blood, urine, buccal cells, and tumor tissue biospecimens. Cohort follow-up is reaching the most informative phase and is a unique resource for scientific aims that integrate exposures over the life course, including diet, other lifestyle variables, biomarkers, genetic predisposition and mediating variables, in relation to cancer risk and survival.

Liquid Biopsy for Treatment Stratification of IDH1.R132H and EGFRVIII Mutant Gliomas 
NCI - 1U01CA230697-01 
PIs: Bob S. Carter (MGH), Johan Skog (Exosome Diagnostics)

Brain tumors are extremely difficult to treat and cause patients to lose important normal brain function and have a low survival rate. Better ways are needed to diagnose brain tumors, which would allow patients to have more effective therapies and less invasive procedures for diagnosis. In this project we are developing a liquid biopsy for brain tumors which would allow a blood test to be used to diagnose and help guide treatment for these difficult tumors. This would greatly improve the care of patients with this disease.

Using Patient-Derived Models to Understand Drug Responses in SCLC 
NCI - 1U01CA220323-01A1 
PIs: Nicholas J Dyson (MGH), Anna Flora Farago (MGH)

Small cell lung cancer (SCLC) afflicts over 30,000 patients per year, and is rapidly fatal in 95% of cases. In most cases, chemotherapy is the only option to prolong survival. We have developed a method to extract SCLC tumor cells from patient blood samples and grow them in mice. The responses of these mouse-born human tumors to cancer therapy mirror the responses of the patients themselves, and can be used compare the effectiveness of different treatments. Here we will use these tumor models to compare approved therapies for SCLC with promising experimental agents. This work may provide the basis for new therapeutic approaches in SCLC.

The Cellular Geography of Therapeutic Resistance in Cancer 
NCI - 1U2CCA233195-01 
PIs: William Nicholas Haining (DFCI), Aviv Regev (Broad Institute)

The majority of patients die from cancer because their tumors stop responding to the treatments that are available – the tumors become resistant to therapy. This proposal will form a Research Center from major cancer centers and research institutions in Boston, Stanford and Princeton to study: each type of cell that exists in breast, melanoma and colon cancer and how they interact in order to find out what is altered in tumors that are treatment resistant. We hope that these studies will help develop: new tests that can identify patients at risk for becoming resistant to their cancer therapies; and new treatment strategies to overcome resistance and improve the outcome for patients with cancer.

The Center for Synovial Sarcoma Biology and Therapeutics 
NCI - 1U54CA231638-01 
PIs: Cigall Kadoch (DFCI), Sirano Dhe-Paganon (DFCI), Ali Shilatifard (Northwestern) 

Synovial sarcoma is a highly aggressive soft-tissue cancer for which there exist no effective targeted therapeutic approaches despite the pathognomonic, genomically well-defined molecular lesion hallmark to every case: the SS18-SSX fusion. Understanding the function of the SS18-SSX fusion in the context of the macromolecular machine to which it binds and hijacks, as well as the features of the chromatin landscape which are uniquely permissive of these activities, represent the most critical next steps and are at present major barriers to therapeutic progress. Our Center on Synovial Sarcoma Biology and Therapeutics seeks to challenge existing paradigms, efficiently define the underlying biology, and to present the field with novel, highly-specific targeted therapeutics to combat this aggressive and devastating disease.

MUC1-C is a Target for Reversing Immune Evasion and Resistance to Immunotherapies
NCI - 1U01CA233084-01
PIs: Donald W Kufe (DFCI), Kwok Kin Wong (NYU)

The MUC1-C oncoprotein is aberrantly overexpressed in human carcinomas and activates a program of immune evasion. However, no therapeutic approaches have been developed clinically against this highly important cancer target. In addressing this unmet need, the proposed research focuses on the development of agents directed against the MUC1-C extracellular and cytoplasmic domains. The goal of these studies is to develop clinical candidates that target MUC1-C as novel immunotherapeutics for treatment of solid tumors.

Multi-Pathway DNA Repair Capacity Measurements in Lung Cancer Patients and Healthy Controls 
NIEHS - 1U01ES029520-01 
PIs: Zachary David Nagel (HSPH), David C Christiani (HSPH), Bevin P. Engelward (MIT)

Aberrant DNA repair capacity is associated with cancer risk, however the available tools measuring DNA repair have been challenging to implement in population studies and often limited to a single repair pathway. We will use a combination of genomics approaches and new genome integrity assays, including recently developed fluorescence multiplex host cell reactivation (FM-HCR) assays and CometChip to make comprehensive assessments of DNA repair capacity in multiple pathways in lymphocytes from healthy individuals and lung cancer patients undergoing radiation therapy. By revealing mechanisms by which deficiencies in genome maintenance may contribute to cancer risk and the severity of clinical radiation sensitivity, this work may open the door to new personalized cancer treatment and prevention strategies.

SIMPRO Research Center: Integration and Implementation of PROs for Symptom Management in Oncology Practice 
NCI -1UM1CA233080-01 
PIs: Debora Schrag (DFCI), Raymond U Osarogiagbon (Baptist Cancer Center), Sandra L Wong (Dartmouth) 

Electronic tracking of patient-reported outcomes (ePROs) has been shown to reduce symptom burden related to cancer treatment, however, evidence for the effectiveness of these systems is limited to large cancer centers and optimal strategies for implementation are uncertain. The proposed 6-site Research Center will adapt existing ePRO symptom management systems, integrate them into an EHR and conduct a pragmatic cluster randomized trial with stepped wedge rollout to investigate the effectiveness of ePRO monitoring to alleviate symptom burden following major cancer surgery or during receipt of palliative chemotherapy. The project will focus on implementation outcomes so that knowledge about the strategies that facilitate adoption and sustainability can inform deployment of this intervention in other contexts.

The Center for Therapeutic Targeting of EWS-Oncoproteins 
NCI - 1U54CA231637-01 
PIs: Kimberly Stegmaier (DFCI), Scott A Armstrong (DFCI)

Overall Ewing sarcoma, an aggressive malignancy of the bone, remains incurable and understudied despite discovery of the oncogenic EWS-ETS fusion proteins that drive tumorigenesis 30 years ago. Understanding the biology and mechanisms of action of EWS-ETS oncoproteins will provide an avenue to develop therapeutic strategies that involve specifically inhibiting the fusion protein, their interacting partners and the core transcriptional circuitry that they drives to promote oncogenesis. Research in this FUSONC2 Center will identify new targets and develop new therapies, thus developing the fundamental preclinical knowledge and tools to more effectively treat this devastating disease.