Cancer Drug Discovery Jump to: SRI's marketed and potential new therapeutics for cancer treatment A growing body of evidence suggests hypoxic cells can directly affect a number of malignant phenotypes, including therapeutic resistance, sustained angiogenesis, evasion of programmed cell death, tissue invasion and metastasis, and 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. SRI's discovery 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. We 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. We are currently investigating whether c-Jun/AP-1 and HIF-1 cooperate to regulate gene expression in hypoxic and anoxic tumor microenvironments. Metal transcription factor-1 (MTF-1) is 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. Our research is focused to clearly define the mechanisms associated with MTF-1 activation by hypoxia, including analysis of potential signaling pathways, phosphorylation events, regulation of the redox state of the MTF-1 DNA binding domain, and nuclear translocation, and to identify other hypoxic stress genes that are controlled by MTF-1. We are using 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 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 Immunology Program 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. Our primary research is directed toward understanding mechanisms of activation of the Dendritic Cells (DCs) critical for the induction of primary immune responses. SRI has a significant track record in discovering 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: 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. Our 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 trails for small-cell lung cancer, mesothelioma and non-Hodgkins lymphoma. Our steroid research programs have yielded several potential drug candidates, including SR 16234, a steroidal antiestrogen selective estrogen receptor modulator (SERM) discovered at SRI and currently in Phase II trials for advanced breast cancer. SR 4554, a nitroimidazole, was discovered as a noninvasive probe for tumor hypoxia and is currently in Phase I clinical trials at Cancer Research UK. Our preclinical pipeline consists of four drugs in various stages of preclinical development:
In addition to these preclinical candidates, we continue to discover new antitumor agents against novel targets. These include
Our active research programs help us develop new technologies in the forms of intellectual property, in vitro assays, and in vivo models that we offer to our clients.
Last Updated Sep 14, 2007 |
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