Cancer Drug Discovery
A growing body of evidence in cancer drug discovery efforts suggests hypoxic (oxygen-deficient) cells can directly affect a number of malignant phenotypes, including:
Sustained angiogenesis test
Evasion of programmed cell death
Tissue invasion and metastasis
Self-sufficiency in growth signals
This scenario is supported by clinical studies that correlate hypoxia with poor prognosis in a number of solid tumor types. These hypoxia-dependent phenotypic alterations are believed to involve, in part, a set of diverse hypoxic stress genes whose expression is controlled by specific hypoxia-sensitive transcription factors.
Stress environments, such as those found in hypoxic tissue, represent physiological differences between tumor and normal tissue. Through cancer drug research, SRI discovered that hypoxia and reoxygenation stimulate expression of the c-jun proto-oncogene in human squamous carcinoma cells suggested that a proto-oncogene can also influence hypoxia-dependent tumor phenotypes.
SRI subsequently found that the induction of c-jun expression and c-Jun phosphorylation by hypoxia has two components: a late component completely dependent on the transcription factor HIF-1 and an early component that is independent of HIF-1. SRI is investigating whether c-Jun/AP-1 and HIF-1 cooperate to regulate gene expression in hypoxic and anoxic tumor microenvironments.
MTF-1 Activation by Hypoxia
Metal transcription factor-1 (MTF-1) activated by hypoxia and tumor expansion in hypoxic mouse fibrosarcomas has been shown to require MTF-1 expression. This ubiquitous transcription factor controls a number of hypoxic stress genes that, if overexpressed, could contribute to the development of clinically important malignant phenotypes in tumors containing transiently hypoxic microregions. SRI’s research is focused to clearly define the mechanisms associated with MTF-1 activation by hypoxia, including:
Analysis of potential signaling pathways
Regulation of the redox state of the MTF-1 DNA binding domain
Identification of other hypoxic stress genes controlled by MTF-1
SRI researchers use both tumor xenograft and in vitro models investigate the functional significance of hypoxia-mediated activation of MTF-1 in malignant progression.
Another key research focus is angiogenesis. Cancer has been described as a wound that never heals. Actively growing tumors become coated with fibrin, the provisional matrix for wound healing. The fibrin clots attract an influx of host tissue, leading to matrix formation and the development of new vasculature. Whereas wound healing progresses to form scar tissue and complete remodeling, tumors continue to use the early stages of the healing cascade to recruit host tissue and form new blood vessels. We are investigating the mechanisms by which tumors avoid tissue remodeling and prolong angiogenesis.
SRI's Center for Immunology and Infectious Diseases has targeted cancer as a major area of focus for its research effort. The group's main interests focus primarily on the roles of cells and soluble factors that regulate innate immunity and the transition to adaptive immune responses. Primary research is directed toward understanding mechanisms of activation of the dendritic cells critical for the induction of primary immune responses.
SRI has a significant track record in cancer drug discovery to identify potential new therapeutics for cancer treatment. Our rich cancer drug pipeline consists of one marketed drug, four in clinical trials, four in various stages of preclinical development, and oncology research programs:
SRI’s Marketed Cancer Drug Treatments
The retinoid Targretin® (bexarotene) is currently used clinically for cutaneous T-cell lymphoma and is being explored for other cancers. The novel hypoxic cytotoxin, tirapazamine, discovered in collaboration with Stanford University researchers, is currently in Phase III clinical trials against cervical cancer, alone and in conjunction with radiotherapy.
Cancer Drugs in Clinical Trials
SRI’s longstanding programs in antifolates led to the discovery of edatraxate and pralatrexate (10-propargyl-10-deazaaminoterin, PDX). PDX, discovered in collaboration with Memorial Sloan Kettering and Southern Research Institute, is currently in Phase II clinical trials for small-cell lung cancer, mesothelioma and non-Hodgkin’s lymphoma.
Cancer Drugs in Preclinical Development
SRI has a significant track record in cancer drug discovery and development, as well as identifying potential new therapeutics for cancer treatment. Our preclinical pipeline consists of several drugs in various stages of preclinical development, including
SR16157 Dual Estrone Sulfatase / ER Antagonist for Breast Cancer Treatment
SR16388 Antiangiogenic, HIF-1α Inhibitor
TAS-108 Novel Steroidal Antiestrogen for Treatment of Breast Cancer
Cancer Drug Research Programs
SRI continues to perform cancer drug development, and discover new antitumor agents against novel targets, including
Green tea analogs as cancer therapeutics and chemopreventives
Peroxisome proliferator-activated receptor ligands for anticancer applications
Active research programs help SRI develop new technologies in the forms of intellectual property, in vitro assays, and in vivo models that are offered to clients.
Using synthetic lethality to ID biomarkers for targeted anti-cancer drugs.
SRI is developing a new therapeutic agent for influenza virus infections.
SRI has developed a promising new treatment for this cancer of the immune system that affects plasma cells in bone marrow.
SRI is identifying candidates for advanced therapies in multiple disease areas by developing compounds from synthetically optimized, natural dietary products.