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:

• Therapeutic resistance

• Sustained angiogenesis

• 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

• Phosphorylation events

• Regulation of the redox state of the MTF-1 DNA binding domain

• Nuclear translocation

• 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.

Angiogenesis

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 Autoimmune and Inflammatory 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.