Cancer is a descriptive term for more than 100 diseases characterized by uncontrolled cell division and growth. Cancers kill by interfering with normal organ function e.g. lungs or brain. In most instances cancers do the worst of their damage far beyond their site of origin. The spread of cancer via blood or lymphatics, to distant sites is known as metastasis and the distant tumors are known as metastases. For example cancer that originates in the breast is most often fatal when it spreads to the lungs or brain and colon cancer when it spreads to the liver. Unsophisticated observers will often say, that a relative had “colon cancer but then it changed to liver cancer". In the medical nomenclature cancers are referred to by their tissue of origin.
Cancers spread through complex though incompletely understood anatomical and biochemical mechanisms. Like normal cells cancerous ones need nutrients. Also like normal cells tumors need a blood supply to grow larger than a rather insignificant size. At this stage the difference between cancerous and normal tissues creates an opportunity for therapeutic intervention.. The vascular(blood vessel) formation in tumors is qualitatively different from that in normal vessels. It is more leaky and is also dependent on the protein know as Vascular Endothelial Growth Factor (VEGF) for its growth and maintenance in contrast to adult normal vessels which are much less so.( The use of inhibition of VEGF and other mediators of tumor spread and growth after spread is a highly active area of research and development. Review HERE- The eye disease associated with diabetes, known as retinopathy is also characterized by the rapid development of new blood vessels and is also being studied with VEGF inhibitors.)
Angiogenesis (formation of blood vessels)is a complex process that is mediated by
the endothelial cells that line blood vessels and.
Targeting the tumor vasculature may be a more effective
therapeutic strategy than targeting the tumor itself for
a number of reasons: Among these are the instability of other targets over time in the rest of the cancer genome, and the relatively low therapeutic index of conventional cancer agents as well as being a unique and complementary target. Nonetheless cancer cells are the consummate adapters,and it is fitting that trials of multiple compounds targeting tumor vasculature or metastases are underway. The following Table gives a list of clinical trials that have been ongoing in this field-as Derek Lowe HERE wrote in such a timely fashion there is a high failure rate in this clinical area as in other ant tumor areas..
Genentech in a landmark study of 900 patients found that median survival in patients with metastatic colorectal cancer had survival of 20 months vs. 15 months when an antibody to VEGF(brand name Avastin) was added to existing established chemotherapeutic regimens. This is an enormous increase and in Dec the FDA agreed to give the drug a priority review. I expect it will be approved sometime in 2004.
From a Gententech press release.
" Based on preclinical and clinical studies showing that VEGF plays a broad role in a range of cancers, Genentech is pursuing a late-stage clinical development program with Avastin evaluating its potential use in metastatic colorectal, renal cell (kidney), breast and non-small cell lung cancers. Avastin is also being evaluated in earlier stage trials as a potential therapy in pancreatic, prostate, ovarian, melanoma and several types of solid tumor cancers and hematologic malignancies. To date, more than 2,000 patients have been treated with Avastin in clinical studies." This is drug development as it should be done.
My sleeper bet to push Genentech in this arena in several years is the VEGF trap from Regeneron (partnered with Avents. In this case a receptor to VEGF is coupled to a molecule that encourages clearance of VEGF from the bloodstream. i.e. a trap. Although only in phase I its activity biochemically and in preclnical models impressive.
Can tumors get around the use of VEGF as a source of new blood vessel stimulation for example with Fibroblast Growth Factor? Can they lie low and dormant-probably. Combination with agents which kill tumor cells is the logical complentary approach, as Genentech has done. Treating patients earlier will I hope result in more true cures rather than just increased survival. Of course that is the hope with all new cancer agents.
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