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Current Phase

The Broad Institute

Principal Investigator 
Stuart L. Schreiber, Ph.D.

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Targeting Vulnerabilities of Therapy-resistant Cancer Cell States with Small Molecules

Targeted therapies and immunotherapies (immune checkpoint inhibitors) have been the most transformative advances in cancer treatment in the last several years. However, these therapies, like traditional chemotherapies, eventually result in tumor resistance to therapeutic attacks on their vulnerabilities. Hence, understanding how to avoid or overcome resistance to therapies is essential when developing treatments that are effective over the long term. The CTD² Center at the Broad Institute aims to discover and understand the bases of therapy resistant-state vulnerabilities and exploit these susceptibilities to develop effective combination therapies.

In the preceding phase, the Broad Institute developed powerful new tools and capabilities that enable the community to identify novel cancer vulnerabilities. These capabilities are shared using the Cancer Therapeutics Response Portal (CTRP), which houses a large dataset of compound sensitivity data (concentration-response curves) and has been made available without restriction. Using the CTRP, researchers at this Center found evidence for the existence of at least one common therapy-resistant state associated with mesenchymal characteristics of cancer cells. This state emerges by non-mutational mechanisms after treatment with either chemotherapy or targeted therapeutics across several cancer types. In the current phase, the Center proposes to i. discover common drug-resistant cancer cell states, ii. define vulnerabilities of these cancer cell states, and iii. identify small molecules that can attack these susceptibilities. These studies will be explored in the context of patient-derived cancer models, which will provide a path forward for combination therapies to overcome treatment-resistance.

Columbia University

Principal Investigator 
Andrea Califano, Ph.D.

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Systematic Identification and Pharmacological Targeting in Tumor Dependencies for Precision Cancer Medicine

Cancer is a complex and highly heterogenous disease, hence an individual gene/protein may not represent an effective target for all the sub-clone-specific mutations in a tumor. Indeed, while genetic-based targeted therapy and immunoncology hold great promise, most patients still do not respond, or will eventually relapse with drug resistant tumors, suggesting that the concept of therapeutic targets as single proteins may need to be revisited. Earlier studies revealed that tumor cell state depends on the coordinated activity of a handful of aberrant master regulator (MR) proteins. These proteins form small hyperconnected components termed tumor checkpoint modules (TCM), which are tightly regulated. The aberrant activity of a TCM is induced by genetic or epigenetic (genomic) alterations in upstream pathways. The CTD² Center at Columbia aims to use this TCM/MR-based conceptual framework to elucidate new druggable targets for single agent and combination therapy.

In the preceding phase, Columbia University has shown that comprehensive dissection of tumor-specific gene regulatory layers can help elucidate novel tumor dependency mechanisms. In the current phase, the Center proposes to i. perform network-based analyses of tumor samples (atypical/anaplastic meningioma, SDHBDel gastrointestinal stromal tumors, and metastatic bladder, lung, and colon adenocarcinoma), ii. prioritize and characterize FDA-approved and late-stage investigational drugs by assessing differential tumor checkpoint activity, and iii. evaluate these single and combination targets in patient-derived xenograft and organoid models. These studies provide a mechanistic approach for precision oncology, where therapeutic targets, associated small molecule inhibitors, and population stratification biomarkers are derived from rigorous and detailed understanding of tumor state regulation and drug-induced modulation.

Dana-Farber Cancer Institute

Principal Investigator 
William C. Hahn, M.D., Ph.D.

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The Dana-Farber Cancer Institute Cancer Target Discovery and Development Center

Efforts to characterize cancer genomes provide a view of the mutations and copy number alterations that occur in human cancers. However, it remains unclear which of these alterations are critical for tumor maintenance, heterogeneity, and the ability to evade the immune system. Identifying genes that are essential for tumor survival and immune evasion will accelerate the development of new molecularly targeted therapeutics. The emerging clinical success of checkpoint blockade is tempered by the reality that most patients do not respond to immunotherapy. New targets are needed to improve tumor responses and guide rational combination immunotherapy to overcome resistance. The CTD² Center at the Dana-Farber Cancer Institute (DFCI) aims to define a comprehensive classification of targets, develop means to rationally identify combination therapies, and discover genes that modulate the response to immunotherapeutics.

In the preceding phase, DFCI developed the bioinformatic tools, methods, and infrastructure to perform genome-scale loss-of-function and gain-of-function screens in human cancer cell lines and patient-derived models to identify and validate cancer targets. In the current phase, the Center proposes to i. systematically investigate genes essential for cancer cell proliferation and survival in colon and pancreatic cancers, ii. interrogate the effects of manipulating combinations of genes and targets to understand the pathways that program malignant transformation, and iii. identify cancer driver genes that enable tumor cells to evade the immune system to uncover new immunotherapy targets and develop rational combinations. These studies will provide functional insights that complement genomic data to identify potential targets and facilitate the translation of this information into the development of therapeutics and diagnostics. The data and methodological approaches used by this Center will be readily available to the CTD² Network and scientific community.

Emory University

Principal Investigator 
Haian Fu, Ph.D.

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Systematic Discovery of Neomorph Protein-Protein Interactions in Cancer for Oncogenic Pathway Perturbation

Genomic mutational landscape offers a unique opportunity to distinguish cancer cells from normal cells, with re-wired oncogenic pathways and networks for therapeutic interrogation. Current cancer genomics efforts are largely centered on identifying cancer-causing genes as therapeutic targets and biomarkers. However, a large number of gene mutations give proteins new capabilities to bind cellular proteins and create new signaling pathways that drive tumor growth. Hence, understanding how to leverage these genomic changes at the mutated amino acid resolution for cancer-specific target discovery, and how to rapidly translate this knowledge into genotype-directed cancer therapies for precision oncology, remains a daunting and urgent challenge. The CTD² Center at Emory University aims to understand the functions of genomic mutations in cancer etiology through systematic interrogation of protein-protein interactions (PPIs) for target identification, validation, and therapeutic discovery across solid and hematological cancer types.

In the preceding phase, the Center developed a sensitive live cell-based biosensor platform coupled with bioinformatics pipeline for exploring PPIs in a high throughput format. This quantitative High Throughput differential Screening platform, termed qHT-dS, enables comparative screening of wild type and mutant driver genes. This platform can be used to discover mutant allele-specific gain-of-function (neomorph) oncogenic PPIs (neo-PPIs). In the current phase, Emory University’s CTD² Center aims to leverage rich genomic mutation data to discover and validate cancer-specific PPIs as targets and pathway perturbagens to accelerate patient-centered therapies. To accomplish this, the Center proposes to i. identify and validate cancer mutation-created neo-PPIs through differential screening with the qHT-dS technology platform, ii. identify small-molecule perturbagens of selected neo-PPIs and understand the drug resistance mechanism, and iii. improve and implement informatics pipeline for streamlined data analysis and integration of genomics information with neoPPI-mediated oncogenic networks and therapeutic responses. These studies will provide potential molecular mechanisms and reveal promising cancer-specific targets for genotype-directed therapeutic discovery.

Fred Hutchinson Cancer Research Center

Principal Investigator 
Christopher Kemp, Ph.D.

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Personalized Cancer Models to Discover and Develop New Therapeutic Targets

A major goal of personalized oncology is to use a tumor’s DNA sequence, gene expression, or other molecular data to inform patient care. Large-scale molecular characterization studies now provide a comprehensive view of the genomic landscape of most human cancers. However, many commonly mutated cancer genes are difficult to target with drugs, and even for genes that might be targetable, it is not clear which one should be prioritized or which drug would be effective for any given patient. Identifying actionable gene targets that are clinically effective in the context of genotypic and phenotypic heterogeneity of tumors remains a major challenge. Moreover, even in cases where targeted therapy works, development of resistance is common, which further highlights the need for additional targeted agents and effective drug combinations. To address these challenges, the CTD² Center based at the Fred Hutchinson Cancer Research Center (FHCRC) developed an approach whose main innovation is functional genomic and drug profiling of patient-derived tumor cells to identify gene targets and candidate drugs with associated biomarkers for preclinical development.

In the preceding phase, the FHCRC Center developed and optimized a pharmaceutical industry grade, array-based high-throughput siRNA and drug screening platform which accurately and efficiently identifies tumor- and genotype-specific vulnerabilities. In the current phase, the Center proposes to i. identify cancer- and genotype-specific therapeutic targets (e.g. synthetic lethal genes) and effective drug combinations to overcome drug resistance using both isogenic and patient-derived tumor cell cultures, ii. develop novel computational approaches and informatics tools to prioritize gene targets with associated biomarkers using large scale data sets, and iii. validate prioritized targets with orthogonal assays in genomically characterized patient-relevant tumor models of increasing complexity and heterogeneity. The Center will initially focus on pancreatic and ovarian cancer with capabilities to extend to additional cancers. These studies will nominate novel targets suitable for drug development and propose more effective therapeutic strategies for several cancer types, particularly for advanced and chemotherapy-resistant tumors.

Johns Hopkins University

Principal Investigators 
Joel S. Bader, Ph.D. 
Andrew Ewald, Ph.D.

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Pathway Discovery and Target Validation for Outgrowth of Breast Cancer Metastasis

Majority of cancer deaths are attributable to metastasis, rather than growth of the primary tumor. Tumors are heterogeneous at the genetic, epigenetic, and phenotypic levels; thereby effective cancer treatments are limited. Current diagnostic approaches do not allow individualized assessment of metastatic recurrence risk nor do they allow effective therapies for metastatic cancers. Breast cancers have few common mutations, and each tumor seems a unique mixture of different low frequency mutations. In breast cancer, metastatic recurrence may occur years to decades after treatment; hence, breast cancer presents a unique research opportunity to improve patient outcomes if effective anti-metastatic therapies could be developed. The CTD² Center at Johns Hopkins University (JHU) aims to combine advances in experimental (Ewald) and computational (Bader) methods to interrogate the metastatic process and systematically dissect the genetic basis of breast cancer.

This Center has developed and applied computational methods to connect quantitative features to their genetic basis across multiple complex human diseases. The Center aims to use a pipeline that relies on organoids from primary human breast cancer tissue to model several distinct steps of metastasis. The Center plans to combine organoids developed from primary human breast tumors with real-time imaging to convert the process of cancer progression into quantitative phenotypes that can be dissected systematically by genomics technologies. To accomplish this goal, the Center proposes to i. identify complex features (or molecular correlates) in primary human breast tumor organoids required for the initial metastatic process, ii. utilize network analysis techniques to prioritize and validate if these candidate targets are required for metastatic growth in the organoid system and patient-derived xenograft models, and iii. modulate candidate targets with chemical and genetic perturbagens from the CTD² Network and other drug discovery efforts. These studies will identify actionable targets for preventing metastatic recurrence or treating patients with established breast cancer metastases.

Oregon Health and Science University - 1

Principal Investigators 
Brian J. Druker, M.D.
Adam Margolin, Ph.D.
Jeffrey Tyner, Ph.D.

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Functional Genomic Discovery of Pathway Targeted and Immune Modulatory Therapeutic Combinations in Hematologic Malignancies

Chemotherapies and targeted therapies are a major focus of drug development for acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), but the majority of patients eventually develop resistance to these treatments. Hence, there is a need to better understand the pathways underlying drug resistance and identify novel drugs or combinations of drugs that can effectively inhibit these pathways. The CTD² Center at Oregon Health and Science University (OHSU-1) aims to take advantage of computational, experimental, and clinical expertise to infer mechanisms underlying drug resistance in AML and CLL and understand the pathways to predict effective drug combinations.

Through Beat AML and other programs, OHSU-1 has amassed a large cohort of patient samples with genomic, functional, clinical, and immune annotation. The Center plans to use this unique and large dataset to elucidate the molecular processes underlying drug sensitivity and resistance in AML and CLL patients. To achieve this goal, OHSU’s CTD² Center proposes to i. develop an integrated computational framework, Predictors of Cellular Phenotypes to guide Therapeutic Strategies (PRECEPTS), ii. create a discovery resource of 400 leukemia patient samples with genomic and immune profiling and ex vivo genome-wide functional CRISPR/Cas screens, and iii. validate the predicted targets/biomarkers and test combinations of therapies to minimize or eliminate drug resistance by ex vivo testing. The proposed studies will have direct translational relevance in selecting novel treatment strategies for clinical trials and will be of benefit to other CTD² Centers as well as the scientific community at large.

Oregon Health and Science University - 2

Principal Investigators 
Gordon Mills, M.D., Ph.D.

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Integrative Bioinformatics and Functional Characterization of Oncogenic Driver Aberrations in Cancer

Large-scale national and international cancer genomic studies are generating a compendium of tumor associated genomic alterations. Prioritizing these alterations as the most promising therapeutic targets for drug development is a major challenge. Although much is known about the function and clinical impact of recurrent “hotspot” aberrations in well-known cancer genes, less is known about which and how the more abundant, low-frequency mutations contribute to tumor progression. Evaluation of low-frequency alterations is difficult as they may indirectly influence tumor progression by modifying activities of concurrent driver aberrations. Differentiating between driver vs passenger gene alterations is also tricky as the driver activity is determined by the context of a given cancer. Hence, translation of tumor genomic datasets into effective cancer therapeutics will require new experimental systems to inform the functional activity of aberrations in the relevant biological context encompassing inter- and intra-tumoral heterogeneity. The CTD² Center based at the Oregon Health and Science University (OHSU-2) will use state-of-the-art, high-throughput informatic and experimental approaches to functionalize oncogenic driver genes and determine the effects of single and combination drug therapies on tumor heterogeneity, as well as elucidate underlying mechanisms and therapeutic liabilities generated by driver aberrations.

In the preceding phase, the Center developed high-throughput gene cloning platforms and engineered numerous mutant and fusion genes for functional evaluation and delivery. In the current phase, OHSU-2 proposes to i. implement an algorithmic framework for prediction of oncogenic, gain-of-function driver aberrations of glioblastoma multiforme, pancreatic ductal adenocarcinoma, and epithelial ovarian cancer, ii. execute context-specific functional screens for the selection of single and combinatorial gene drivers of tumor progression and determine the effects of single and combination drug therapies on tumor heterogeneity and drug resistance, and iii. elucidate underlying mechanisms and therapeutic liabilities generated by driver aberrations. These studies will improve the understanding of how cancer gene aberrations affect downstream function within the protein and cellular pathways in cancer.

Stanford University

Principal Investigators 
Calvin J. Kuo, M.D., Ph.D.
Hanlee Ji, M.D.
Christina Curtis, Ph.D.

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Organoid-based Discovery of Oncogenic Drivers and Associated Transformation Mechanisms

Cancer has extremely complex origins with a multitude of genomic and epigenomic alterations in interaction with cell-extrinsic stromal and environmental factors. Large-scale cancer genomic studies have generated a torrent of multi-scale omics data spanning mutations, gene expression, epigenetics, and proteomics. The data has revealed a daunting, highly plastic cancer landscape with tremendous interpatient variation requiring precision medicine approaches. In turn, this has generated an acute need for scalable cancer models to functionally characterize putative oncogenic driver events in a context dependent manner and elucidate the molecular drivers of treatment response. The CTD² Center at Stanford University aims to apply state-of-the-art systems biology and bioinformatics to scan large-scale cancer genomic characterization studies. These approaches provide guidance in nominating candidate genes for functional validation in cancer.

In the preceding phase, Stanford developed in vitro 3D “organoid” culture methods (air-liquid interface) for cancer modeling. Organoids are three-dimensional miniature organs retaining tissue architecture and multilineage differentiation and represent a potentially transformative approach for functional interrogation of large-scale cancer genomic/epigenomic data sets. In the current phase, the CTD² Center plans to i. prioritize amplified or deleted copy number alterations “outliers” from The Cancer Genome Atlas study for functional validation in lung, colon and stomach organoids, ii. functionally validate hypomethylated oncogene candidates and identify loci exhibiting non-linear relationships between hypomethylation and overexpression, and iii. study tumor genome/epigenome evolution and origin of cooperating oncogenic events. The Center’s focus on post-genomic systematic and functional interrogations translate the genomic findings into clinical application.

University of California San Diego

Principal Investigators 
Pablo Tamayo, Ph.D.
Ezra Cohen, M.D.
Dan S. Kaufman, M.D., Ph.D.
Jill P. Mesirov, Ph.D.

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A Rational Systematic Approach to Find Combinations of Pharmacologic and Immune Therapies that Target Identifiable Oncogenic States

Tumors have biological and clinical heterogeneity, even when they share the same mutations. Standard cancer classification is based on the anatomic site of tumor origin or the mutation status of known drivers; whereas, oncogenic state is defined as a functional status that is activated by specific signaling pathways and provides a more rational basis to identify therapeutic interventions. In addition, the wide variability of clinical responses to immunotherapy, and the onset of immune escape, are becoming a formidable obstacle to fully realize the potential of many new and effective immunotherapies. The CTD² Center at the University of California San Diego (UCSD) aims to identify oncogenic cell states and characterize the most salient genomic and immune hallmarks to infer optimal combinations of pharmacologic and immunological perturbagens.

The Center’s preliminary data suggested that in each identifiable oncogenic state there is a close interplay between activation of oncogenic elements, cellular pathways, and the immune microenvironment. To validate this data, the Center proposes to i. select 5-10 oncogenic states and identify state-specific immunological targets, including immune checkpoints, neoantigens/anti-tumor epitopes, antibodies, and chimeric antigen receptors for cellular immunotherapy, ii. develop a multifactorial predictive model for each oncogenic state to identify the most effective combinations of pharmacological and immunological perturbagens, and iii. validate these perturbagens in isogenic cell systems, cancer cell lines, genetically engineered mouse models, and patient-derived xenografts. These studies will lead to the development of novel treatment strategies and provide the foundation for a new generation of more comprehensive, functional-based, precision oncology approaches.

University of California San Francisco - 1

Principal Investigators 
Michael McManus, Ph.D.
Jonathan Weissman, Ph.D.
Trevor Bivona, M.D., Ph.D.
Sourav Bandyopadhyay, Ph.D.

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The Cancer Target Discovery and Development Network at UCSF

The major challenges of developing effective cancer treatments are drug resistance, tumor heterogeneity, and tumor evolution. Molecular characterization studies have identified a large number of genetic alterations in many cancer types. However, how these alterations contribute to cancer is not completely understood; hence, systematic exploration of the functional roles of these alterations is critical for the development of effective cancer therapeutics. The CTD² Center at the University of California San Francisco (UCSF-1) aims to combine in-depth mining of large-scale genomic data and systems biology analyses to characterize functional roles of genetic lesions, both alone and in combination, in driving tumor formation and growth.

In the preceding phase, UCSF-1 developed CRISPR screening and ultra-high-throughput single cell protocols to perform comprehensive quantitative screens and identify genes essential for cancer initiation, maintenance, and possibly metastasis. In the current phase, the Center proposes to i. utilize the novel single-cell CRISPR platform to functionalize the cancer genomic data and associate genes with novel drug resistance mechanisms, ii. organize recurrently altered cancer genes from genome characterization initiatives into pathways associated with clinical resistance to understand functional impacts of inter- and intra-tumoral heterogeneity, iii. develop and apply methodologies to annotate pathways critical for tumor microenvironment interactions, and iv. construct genetic epistasis maps to identify and distinguish cancer drivers vs. passengers to uncover the optimal combinations of perturbagens with the potential to eliminate all cancer cells, despite their clonal heterogeneity and environmental context.

University of California San Francisco - 2

Principal Investigators 
William Weiss, M.D., Ph.D.
Allan Balmain, Ph.D. 
Matthew Krummel Ph.D.

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Integrating Targeted and Immunotherapy to Treat Genetically Heterogeneous Cancers

Cancer immunotherapy has attracted enormous attention by the recent success of immune checkpoint blockade inhibitors, such as anti-cytotoxic T lymphocyte antigen-4 and the anti-programmed death-1 antibodies. However, only a fraction of patients responds to checkpoint inhibitors. A major challenge is to improve these response rates by understanding the variables that influence clinical outcomes. Combining immune modulatory drugs, or adding these to targeted agents or chemotherapies, may improve clinical responses. The goal of the CTD² Center at the University of California San Francisco (UCSF-2) is to identify, validate, and integrate targeted therapy with immunotherapy that most efficiently attack both tumor cells and the immune components in advanced cancers.

In the preceding phase, the Center developed immunocompetent mouse models that represent different ends of the spectrum of tumor types. Carcinogen-induced squamous carcinomas with high mutation load, but variable responses to immunotherapy, are “hot” tumors that present more or stronger antigens, or that encourage infiltration by immune effector cells. On the other hand, genetically engineered neuroblastoma with very low mutation burden are immunologically “cold” tumors that do not engage the immune system. In the current phase, UCSF-2 aims to address mechanisms of immune escape by exploiting these unique mouse models that mirror major genetic categories of human cancer – high vs low mutation load and strong vs weak immune infiltrate. Ongoing experiments aim to make immunologically “cold” tumors into “hot” tumors. To achieve this goal, the Center proposes to i. perform CRISPR/Cas9 screens in immune cells (monocytes and T cells) of the tumor microenvironment to identify genes associated with immune cell entry and effector functions, ii. use genetic or pharmacological perturbation of existing and newly identified candidate genes to determine pathways that improve/drive antigen presentation and abundance, and iii. implement computational analysis to exploit gene expression networks of existing databases, to prioritize potential targets that enhance immune responses. These studies will improve immunotherapies and generate lead targets, reagents, and diagnostics for cancer treatment.

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