Targeting the microenvironment of pancreatic cancer: overcoming treatment barriers and improving local immune responses

Historically, patients diagnosed with metastatic pancreatic cancer have faced a grim prognosis. The survival benefit seen with systemic chemotherapies and even combinations thereof have been disappointing. However, growing data suggest that the microenvironment of pancreatic cancer may be contributing to this poor prognosis. This microenvironment has a dense fibrotic stroma, and is hypoxic and highly immunosuppressive, all of which pose barriers to treatment. Newer strategies looking to disrupt the fibrotic stroma, target hypoxic areas, and improve local immune responses in the tumor microenvironment are currently undergoing clinical evaluation and seem to offer great promise. In addition to these therapies, preclinical work evaluating novel cytotoxic agents including nanoparticles has also been encouraging. While much research still needs to be done, these strategies offer new hope for patients with pancreatic cancer (AU)

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Review of Three New Agents That Target Angiogenesis, Matrix Metalloproteinases, and Cyclin-Dependent Kinases.

BACKGROUND: Many potential new antineoplastic agents are currently in various stages of clinical development. Three areas of drug development include antiangiogenic compounds, agents that inhibit matrix metalloproteinases, and agents that modulate cyclin-dependent kinases. METHODS: The authors reviewed the available data for endostatin, COL-3, and flavopiridol, each of which is being developed with one of the above-mentioned proposed mechanisms of action. These agents are among the first drugs to reach clinical testing that is focusing on these novel targets. RESULTS: Endostatin has finished preclinical testing and the first human trials are about to be initiated. COL-3 is in phase I testing in several locations. Phase I studies for flavopiridol have been completed and several phase II studies are underway. It is unknown at this point if any of these agents will provide clinical benefit to patients at doses that do not cause unacceptable toxicity. CONCLUSIONS: These agents are currently at various stages of clinical testing. Albeit promising as potential modulators in molecular and biochemical pathways, continued research is needed into the toxicities and clinical usefulness of these agents.