Stuart Schreiber's research focuses on the discovery and use of small-molecule probes (precursors to therapeutic drugs that are used as tool compounds) to explore cell circuitry and disease biology.
Pancreatic Islet Biology and Diabetes
The World Health Organization estimates that up to 35 million people suffer from type 1 diabetes (T1D), the cause of which is unclear and which is not currently preventable. Loss of insulin-producing β cells caused by autoimmune destruction results in dependence on exogenous insulin and risks of complications as a result of lifetime impairment of blood-glucose homeostasis. Currently, no effective pharmaceutical therapies exist for T1D; insulin injections remain the sole means of treatment. Recent research in mice indicates that genetic procedures resulting in an increase in β cell mass can ameliorate diabetes. Thus, small molecules capable of increasing β cell numbers could make good candidates for T1D treatment.
We take a three-tiered approach to increase β cell mass with small molecules. First, we seek to identify inducers of human β cell proliferation by phenotypic screening of human islet cells and by modulating suitable target proteins. Second, we attempt to promote transdifferentiation of other pancreatic cell types to β cells. This aim includes modulating the expression of the transcription factor Pax4 in α cells to convert them to β cells. Finally, we aim to suppress cytokine-induced pancreatic β cell apoptosis, focusing on a novel small-molecule candidate with protective effects.
The student will learn the theory and practice of cell-based assay development for high-throughput screening, including techniques such as cell culture, miniaturized assay performance, and data analysis.
Human Biology and Patient-Based Therapeutics Discovery
Human genetics has revealed many instances of genes having both risk and protective variants in the human population for several diseases, including Crohn's disease (CARD9), Alzheimer's disease (APP), cardiovascular disease (PCSK9), and type 1 and type 2 diabetes (unpublished). We are studying the interaction partners of the proteins encoded by these genes and establishing small-molecule discovery experiments to test therapeutic hypotheses emerging from these "experiments of Nature."
Cancer Dependencies Targeted by Small Molecules
A new approach to the discovery of cancer therapeutics is emerging that begins with the cancer patient. Genomic analysis of primary tumors is providing an unprecedented molecular characterization of the disease. Our mission, as part of the National Cancer Institute’s Cancer Target Discovery and Development (CTD2) Network, is to identify the dependencies that different cancers acquire as a consequence of their genotype and to target them with small molecules. Cancers may become dependent on specific oncogenes (oncogene dependencies) or their interacting genes (non-oncogene codependencies). Cataloging these Achilles’ heels and linking them to the causal genetic alterations will be critically important for therapies that are personalized to individual patients, including combination therapies aimed at targeting multiple dependencies at once. To address this challenge, we created the a public resource, the Cancer Therapeutics Research Portal (www.broadinstitute.org/ctrp).
Specifically, the CTD2 Center at the Broad Institute focuses on the following two areas:
1. Probing acquired dependencies by modulating protein function. The dramatic clinical consequences of linking genetic features of cancers to drug efficacies, including response rates of >80%, are well known, yet these advances today only benefit <1% of cancer patients. Our CTD2 Center relates the genetic features of cancers to small-molecule probe or drug efficacies broadly. Specifically, we are assembling an "informer set" of new and existing small-molecule probes whose members modulate many candidate targets and processes shown to be important for cancer, and we are using this set in screens of 949 cell lines with characterized genotypes to identify the dependencies associated with a given cancer genotype. For identified candidate dependencies, we are undertaking a series of experiments to confirm and substantiate the results to prioritize them for further development.
2. Discovering probes against novel cancer targets. The CTD2 Network also aims to accelerate the development of genetically matched cancer drugs by discovering novel small-molecule probes of candidate cancer targets not yet modulated by small molecules. The goal is to identify these gaps and undertake collaborative probe-development projects involving high-throughput screening, follow-up medicinal chemistry and biology, and mechanism-of-action studies.