This Cooperative Agreement award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides $4,653,104 in funding to the Massachusetts Institute of Technology (MIT) to discover and develop small molecule agents that can modulate the function of the PAX3-FOXO1 fusion oncoprotein, which drives the progression of fusion-positive alveolar rhabdomyosarcoma (FP-RMS), a highly fatal childhood cancer. The project involves a collaborative team of chemical biologists,...
This Project Grant from the National Institutes of Health's National Cancer Institute totaling $668,151 will support the development of highly multiplexed live-cell G protein-coupled receptor (GPCR) arrays for glioma drug discovery. Spectragenetics, Inc. will deploy an automated multiplexed live-cell assay to detect and quantify agonist and inverse-agonist activities against 55 GPCRs known to be upregulated or downregulated in human gliomas. The assay will be used to screen 48 established...
This Project Grant award of $244,228 from the National Cancer Institute's Cancer Detection and Diagnosis Research program (CFDA 93.394) supports a research project at the University of Texas MD Anderson Cancer Center. The project aims to develop a functional proteomics approach to accurately map patient tumor samples to preclinical lung cancer models. Specifically, the researchers will: Expand proteomic profiling of lung cancer patient-derived xenograft (PDX) models using a reverse-phase protein...
This $588,426 Project Grant award, provided by the National Institutes of Health (NIH) Office of the Director under the Trans-NIH Research Support program (CFDA 93.310), aims to investigate how transcription factors efficiently locate and bind to specific DNA binding sites within the crowded nucleus of living cells. The project will employ advanced microscopy techniques to precisely track the 3D diffusion, DNA interactions, and target site discrimination of transcription factors involved in...
The National Cancer Institute (NCI) awarded a $135,594 Project Grant under the Cancer Research Manpower (CFDA 93.398) program to The Leland Stanford Junior University (Stanford University) to develop novel pharmacological approaches to rewire oncogenic gene expression and induce cancer cell death. The key objectives are to: 1) Develop small molecule chemical inducers of proximity (CIPs) that can target and kill aggressive leukemias driven by mixed-lineage leukemia (MLL) fusion oncogenes, and...
The National Cancer Institute (NCI) awarded a 4-year, $554,653 Project Grant (CFDA 93.394 - Cancer Detection and Diagnosis Research) to the Institute for Systems Biology in Seattle, WA for the "RARECYTEFINDER" project. The goal of this project is to develop an advanced, label-free method for the unbiased identification and comprehensive molecular analysis of rare disseminated tumor cells (DTCs) present in liquid and tissue biopsy specimens across various solid tumor types. The...
This Project Grant award from the National Cancer Institute (CFDA 93.398 - Cancer Research Manpower) provides $172,193 to the Dana-Farber Cancer Institute in Boston, MA to conduct research on improving diagnosis and treatment of translocation renal cell carcinoma (TRCC), a rare and aggressive form of kidney cancer. The key objectives are to: 1) Develop a method to characterize subtype-specific gene regulatory elements in TRCC by identifying differentially active transcription factors and their...
This $377,870 Project Grant awarded by the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) supports the development and validation of novel synthetic transcriptional repressors (STRs) capable of directly inhibiting the oncogenic transcription factor MYC. The grant aims to: 1) Optimize STR structures for high-affinity and specific binding to MYC target DNA sequences, 2) Enhance cellular and pharmacologic delivery of STRs while mapping their effects on epigenetic and...
The federal Cooperative Agreement award with ID UM1CA294119 was granted by the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) to The University of Texas Southwestern Medical Center for a project titled "Targeting Transcriptional Addiction in Fusion-Driven Sarcoma". The $2,203,647 award, with a performance period from July 8, 2024 to June 30, 2029, will fund research aimed at identifying and advancing small molecules that target transcriptional fusion...
This Project Grant award from the National Science Foundation (CFDA 47.084 - NSF Technology, Innovation, and Partnerships) provides $275,000 to Altay Therapeutics, Inc., a biotechnology company, to develop novel small molecule therapies that target disease-causing transcription factors for treating chronic illnesses and cancers. The key goals of this SBIR Phase I project are to: (1) determine the toxicity profile of new inhibitors across human cells, (2) measure drug specificity to the target...
SIMULTANEOUS PHARMACOLOGICAL PROFILING OF ONCOGENIC GENE FUSION PROTEINS IN CANCER - RESEARCH SUMMARY THE HUMAN GENOME ENCODES MORE THAN 1,600 TRANSCRIPTION FACTORS (TFS), ALONG WITH ADDITIONAL COFACTORS, CHROMATIN REGULATORS, AND STRUCTURAL PROTEINS THAT COLLECTIVELY EXECUTE THE REGULATORY INSTRUCTIONS ENCODED WITHIN THE NUCLEAR DNA. DYSFUNCTIONS OF THESE PROTEINS, COLLECTIVELY KNOWN AS GENE REGULATORY PROTEINS (GRPS), ARE KNOWN TO DRIVE MULTIPLE DISEASES SUCH AS CANCER, INFLAMMATION-RELATED, AND NEUROLOGICAL CONDITIONS. IN CANCER, THESE PROTEINS ARE FREQUENTLY REARRANGED AND FUSED TO CREATE NEW PROTEINS WHICH CAUSE THE INITIATION AND PROGRESSION OF VARIOUS TYPES OF LEUKEMIA, SARCOMA AND OTHER TUMORS. DESPITE THE IMPORTANCE OF THESE PROTEINS, GRPS HAVE BEEN CONSIDERED UNDRUGGABLE DUE TO CHALLENGES IN MODELING THEIR ACTIVITY IN VITRO. WE HAVE SOLVED THESE SHORTCOMINGS BY IMPLEMENTING AN IN-CELL FUNCTIONAL PROTEOMICS DRUG DISCOVERY PLATFORM THAT QUANTIFIES THE EFFECTS OF SMALL-MOLECULES ON THE ABUNDANCE OF GRPS BOUND TO THE GENOME IN A DIVERSITY OF CELL AND TISSUE TYPES. THE PLATFORM IS BASED ON CHROMATIN EXTRACTION BY SALT SEPARATION, COUPLED TO DATA INDEPENDENT ANALYSIS MASS SPECTROMETRY (CHESS-DIA), WHICH WAS RECENTLY REPORTED. IN THIS PROPOSAL, WE WILL APPLY THIS TECHNOLOGY FOR DRUG DEVELOPMENT OF ONCOGENIC FUSION PROTEINS. FIRST, WE WILL USE MIXED LINEAGE LEUKEMIA (MLL) REARRANGED LEUKEMIA TO PERFORM TECHNOLOGY DEVELOPMENT OF THE ONCOGENIC FUSION PROTEIN PROTEOMICS STRATEGY. MLL REARRANGEMENTS ARE FOUND IN A SUBSET OF AML AND ALL PATIENTS, COMMONLY IN CHILDREN, AND REMAIN CHALLENGING TO TREAT WITH EXISTING THERAPEUTIC OPTIONS. SEVERAL DRUG CANDIDATES FOR MLL-REARRANGED LEUKEMIA ARE CURRENTLY IN CLINICAL TRIALS, AND THESE WILL BE USED TO VALIDATE THE ACCURACY OF THE CHESS-DIA ASSAY FOR REPORTING THE ABILITY OF MLL-TARGETING COMPOUNDS TO DISRUPT THE MLL COMPLEX IN LIVE CELLS. WITH A VALIDATED MLL CHESS-DIA ASSAY, WE WILL THEN CONDUCT A PILOT SCREEN TO PROVE THE ASSAY'S UTILITY IN A SCREENING SETTING, USING THE NATIONAL CANCER INSTITUTE'S MECHANISTIC DIVERSITY COMPOUND SET SUPPLEMENTED WITH KNOWN INHIBITORS OF THE MLL COMPLEX. THESE COMPOUNDS CONTAIN A DIVERSE ARRAY OF BIOACTIVITIES, MANY OF WHICH ACT THROUGH UNKNOWN MECHANISMS. THIS PROVIDES AN OPPORTUNITY TO FIND NEW COMPOUNDS CAPABLE OF DISRUPTING THE MLL COMPLEX. LASTLY, WE WILL USE THE ROADMAP DEVELOPED FOR MLL TO DEVELOP CHESS-DIA ASSAYS FOR MANY OF THE COMMON ONCOGENIC FUSIONS, THEN DEVELOP A METHOD TO UNIFY THESE ASSAYS TOGETHER IN A SINGLE, UNIFIED, IN-CELL ASSAY FOR ONCOGENIC FUSION PROTEINS.