Colon cancer [CRC] is the third leading non-squamous-basal cell cancer in the western world. While it is largely preventable with screening colonoscopy, approximately 150,000 new cases of invasive disease are diagnosed annually in the US, of which one-third die.

Beyond earlier diagnosis (which tends to improve outcomes), post-operative “adjuvant” preventative chemotherapy is also moderately effective in reducing cancer death. Unfortunately, for the vast majority of patients whose cancer has already spread beyond the colon, very few cures are achieved.

Treatment of these individuals is called palliative therapy, and includes a variety of chemotherapy agents—generally given in combination as well as what is referred to as ablation, or the cutting-out/burning/irradiating of unwanted (generally) liver metastases. These treatments are designed to shrink or destroy clumps of tumor cells, or lesions, and thereby improve one’s appetite, nutritional status, feeling of well being, as well as to (hopefully) prolong one’s life.

New molecular biological techniques have identified many of the drivers of cancer cells; these are typically mutated genes that result in increased cell growth (proliferation) or spread (metastases) or make them become resistant to death (apoptosis), or all of the above. This process is often referred to as oncogene addiction, whereby one principal metabolic pathway is unregulated, and drives the tumor cells to grow. With these discoveries, rationally constructed treatments have been developed in order to disrupt the gene signals responsible.

For example, the drug imatinib (Gleevec) will block the main gene product (an enzyme) responsible for the disease chronic myeloid leukemia. Crixotinib blocks the ALK gene product in lung cancer, while vemurafenib will block the BRAF gene product in melanoma. These are all oral agents (pills); while they do not cure these diseases, they can slow down progression of cancers expressing the gene targets responsible, and prolong and improve quality of life substantially.

One such gene pathway in colon cancer is the epidermal growth factor receptor pathway [EGFR], over expressed in over 50 percent of CRC cells. Stimulation of this receptor will subsequently activate intracellular enzyme pathways regulated by genes such as KRAS, PI3CA, and so forth. There are currently two FDA-approved drugs which target the EGFR pathway; these agents have been found to be active in shrinking tumor on their own, and seem to improve the lethal effects (“response rate”) and even patient survival of certain chemotherapy drugs given in combination after the chemotherapy has stopped working.

They likely work by altering the cancer cell metabolism, as well as by coating the cancer cell with antibodies which may lead to immune targeting and cell kill. Unfortunately, mutations in the cancer gene, KRAS [found in 40 percent of colon cancer], appear to cancel this anti-cancer effect of these agents. While they may cause skin rash, they are otherwise generally well-tolerated agents.

Of course, any progress in cancer therapy requires scientific analysis: in the US, this is a highly regulated process, requiring FDA authorization, Institutional Review Board approval, and close independent monitoring oversight. Typically, the finding of efficacy in patients with advanced disease (incurable) often leads to the study of these drugs in earlier cancer settings, where the likelihood of benefit is much higher.

One experimental agent, RO5083945 is a synthetic anti-EGFR antibody which is much more effective in recruiting the immune system to attack targeted EGFR-expressing colon cancer cells.  Preliminary studies with single-agent antibody have shown a clinical benefit in 40 percent of heavily pre-treated (with chemo) refractory colon cancer patients.

We at the Family Cancer Center Foundation are currently actively studying this agent in combination with standard-of-care type therapy; we hope to benefit patients who might have exhausted active and effective treatments, as well as offer hope and maybe significant benefit to patients stricken with this aggressive and fatal illness.

For a complete listing of our clinical trials, visit www.familycancercenter.com

‑ Dr. Donald Gravenor

 www.familycancercenter.com

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