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 decode cancer genotypes so as to read out acquired pathway and oncogene addictions of the specific tumor subtypes, and to identify small molecules that target these dependencies. We are probing the consequences of these alterations on the dependencies or co-dependencies different cancers have on specific oncogenes or their interacting genes (‘oncogene addiction’ and ‘non-oncogene co-dependencies’). 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.
Specifically, the Broad CTD2 Center focuses on:
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 patients suffering from cancer. Our CTD2 Center is relating the genetic features of cancers to small-molecule probe or drug efficacies broadly. Specifically, we are assembling an “Acquired Cancer Dependency Probe Kit” of new and existing small-molecule probes whose members modulate many candidate targets/processes shown to be important for cancer, and we are using this probe kit in screens of ~500 cell lines with characterized genotypes to identify the dependencies associated with a given cancer genotype.
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 to undertake collaborative probe-development projects involving high-throughput screening, follow-up and medicinal chemistry and biology, and mechanism-of-action studies. Our CTD2 investigators are especially interested in projects involving challenging targets such as transcription factors, and chromatin-modifying enzymes.
Recognizing that cancer initiation, progression, metastasis, and drug resistance depend in part on the tumor microenvironment, we are exploring ways to target these mechanisms as well.