Kidney Cancer Drug Delays Disease Progression

The experimental drug BAY 43-9006 (sorafenib) was shown to delay the progression of advanced kidney cancer according to preliminary results from a phase III clinical study. The findings were announced March 21 by the drug's two sponsors, Bayer Pharmaceuticals and Onyx Pharmaceuticals. An independent data monitoring committee for the trial concluded that the study had met its surrogate endpoint resulting in statistically significant, longer progression-free survival in patients taking sorafenib compared with patients taking a placebo.

As a result, the two companies announced plans to file a New Drug Application with the FDA, seeking accelerated approval for sorafenib. They also will pursue completion of the phase III trial toward the primary endpoint of demonstrating whether the drug improves overall survival rates for kidney cancer patients. In addition, the companies plan to submit data from the phase III study at the American Society of Clinical Oncology annual meeting in May.

The multinational trial enrolled over 800 patients with advanced kidney cancer. Half of the patients in the randomized, double-blind study received sorafenib while the other half received placebo.

Sorafenib is a targeted oral therapy with a two-fold method of action, inhibiting both the RAF kinase signaling pathway while also exerting an antiangiogenic effect through inhibition of VEGFR-2 and PDGFR-ß kinases. "BAY 43-9006 has demonstrated both antiproliferative and antiangiogenic properties - two important anticancer activities," reports Onyx. The drug is reported to have moderate-to-low side effects in most patients. The companies also announced plans to test sorafenib for treatment of melanoma.

Collagen VII Mutation Linked to Skin Cancer's Spread

In an experimental model of human squamous cell skin cancer, collagen VII, a protein that helps bind the superficial epidermis to the underlying dermis, has now been implicated in the eventual invasion of squamous cancer cells to other parts of the body. This finding is published in the March 18 Science.

The research team from Stanford University School of Medicine worked with skin keratinocytes and skin cancers from patients with the genetic disease recessive dystrophic epidermolysis bullosa (RDEB), in whom the collagen VII gene is mutated, causing their skin to be fragile and blister. More than 55 percent of RDEB patients die from metastatic squamous cell carcinoma (SCC) by the age of 40, while a subset never develops it.

Examining this disparity, the researchers collected SCC samples from 10 RDEB patients and found that they all had detectable collagen VII expression. However, in 10 RDEB patients who had not developed SCC, 4 skin biopsy samples lacked collagen VII expression. After transducing keratinocytes from RDEB patients with oncogenic retroviruses and injecting them into mice, those keratinocytes from patients lacking collagen VII did not form tumors, but those from patients expressing a collagen VII protein, albeit truncated, formed invasive SCC.

The authors showed that physical interactions between collagen VII and laminin-5, an extracellular basement membrane protein, facilitates SCC invasion, and further demonstrated that an N-terminal fragment of collagen VII, FNC1, was sufficient for tumor formation and invasion. The authors propose that collagen VII or FNC1 may be a novel therapeutic target against tumor invasion.

In a related editorial, however, Dr. Stuart H. Yuspa of NCI and Dr. Ervin H. Epstein, Jr., of the University of California, San Francisco, warn that such a therapy would need to selectively block tumor invasion without weakening the anchor between epidermis and dermis. "We are faced with a possible Pyrrhic victory," they write, "perhaps winning the battle against SCC but losing the battle against the disfiguring skin defects of [RDEB]."

Immunosuppressive Drug Sirolimus Can Inhibit Kaposi's Sarcoma in Kidney Transplant Patients

Researchers at the University of Foggia in Italy have shown that the drug sirolimus (rapamycin) can inhibit Kaposi's sarcoma in kidney transplant recipients while still preventing host-organ rejection. These results, appearing in the March 31 New England Journal of Medicine, suggest sirolimus' dual antitumor and antirejection abilities will make it an effective therapy for transplant patients at risk for developing tumors.

Kaposi's sarcoma is a malignancy associated with uncontrolled growth of blood vessels and frequently results in purple lesions appearing on the skin. The incidence of Kaposi's sarcoma is much higher among organ transplant recipients and AIDS patients, indicating that suppression of the immune system may promote development of this disease. Treating Kaposi's sarcoma in transplant patients is complicated because immunosuppression needs to be maintained in order to prevent host rejection of the transplanted organ.

The immunosuppressive drug sirolimus has been shown to have some antitumor properties in animal and cell-line studies. The researchers, led by Dr. Giuseppe Grandaliano, examined the clinical effect of sirolimus in 15 kidney transplant patients who developed Kaposi's sarcoma. Upon sarcoma diagnosis, the patients stopped receiving cyclosporine and began sirolimus treatment. One month after sirolimus therapy began, the sarcoma lesions began regressing in 12 of the 15 patients, and 3 months after initiation all 15 patients achieved clinical and histological remission. Importantly, the switch in treatment did not provoke any acute episodes of rejection and graft function remained stable during sirolimus treatment.

Rapamycin Agent Improves Response to Low-Dose Cisplatin

The rapamycin-derivative RAD001 (everolimus) dramatically enhanced solid tumor responses to low doses of the DNA-damaging agent cisplatin in a study reported in the March 25 issue of Cell.

Researchers from Novartis and the Friedrich Miescher Institute in Basel, Switzerland, combined RAD001 with cisplatin against cell lines of A549 non-small-cell lung cancer. The most dramatic effects for inducing apoptosis (cell death) in the tumor were found at normally suboptimal doses of cisplatin "with a more than 10-fold difference observed at a concentration where cisplatin alone had no detectable effect," the scientists report. RAD001's additive effect disappeared at higher doses of cisplatin, they add.

Cisplatin and other DNA-damaging agents "have revolutionized chemotherapy against solid tumors" but have been limited in their use by a "narrow therapeutic window combined with severe side effects," the researchers note. Derivatives of the fungicide rapamycin have shown promise by sensitizing tumor cells to respond to lower doses of such chemotherapeutic agents.

"The sensitizing effects of RAD001 on loss of cell viability are presumed to be through inactivation of the mTOR pathway," the scientists comment. To explore that theory, they tested RAD001 on mTOR cell lines. "These findings suggest that RAD001 sensitizes tumor cells to DNA-damaging agents by blocking the upregulation of p21 through inhibition of mTOR," they conclude.

The researchers comment that "targeting mTOR with agents like RAD001 may offer the opportunity to treat p53 wild-type tumors with much lower doses of DNA-damaging agents, thereby reducing side effects while maintaining antitumor efficacy."

Colorectal Screening for African Americans Should Start at Age 45, Panel Urges

A panel of experts from the American College of Gastroenterology (ACG) has recommended that African Americans begin screening for colorectal cancer at age 45 rather than age 50. This was included along with other recommendations aimed at reducing the death and suffering caused by colorectal cancer among African Americans in a special report in the March 2005 American Journal of Gastroenterology.

The report was based on an "extensive review" of the literature on colorectal cancer screening and issues related to health screening in African Americans. This group has the highest incidence of colorectal cancer of any racial or ethnic group in the United States. At the time of diagnosis, African Americans tend to be younger and have more advanced disease as compared with whites. Survival rates in African Americans with colorectal cancer are also lower than in whites.

The proposal to begin screening this population group at age 45 is "very appropriate and fully justified given the high incidence and early age of onset of colorectal cancer in African Americans," comments Dr. Douglas Rex of Indiana University and a past ACG president. "This is just the beginning. As the document states, special efforts are needed to ensure that screening indeed takes place in this high-risk population."

Among other recommendations, the ACG panel endorsed the use of colonoscopy as a first-line screening procedure and urged professional gastroenterological societies to create educational programs to make clinical gastroenterologists aware of facts about colorectal cancer in African Americans.