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The Lancet Oncology

Sunday, December 7, 2008

Combining targeted therapy drugs may treat previously resistant tumors

Blocking two cell signaling pathways leads to dramatic shrinkage of K-Ras-mutated tumors in animal model. This is the conclusion of a team of cancer researchers from several Boston academic medical centers. The team believes that their findings offer a potential treatment for a group of tumors that have resisted previous approaches of treatment with selected targeted therapies.

In their report published in the december issue of Nature Medicine, investigators from Dana-Farber Cancer Institute, a principal teaching affiliate of the Harvard Medical School, Massachusetts General Hospital (MGH) Cancer Center, the original and largest teaching hospital of Harvard Medical School and Beth Israel Deaconess Medical Center (BIDMC) Cancer Center, a patient care, teaching and research affiliate of Harvard Medical School, report that combining two different kinase inhibitors, drugs that interfere with specific cell-growth pathways, led to significant tumor shrinkage in mice with lung cancer driven by mutations in the K-Ras gene.

K-ras, which is part of the ras family of oncogenes which also includes H-ras and N-ras, is involved in the development of a variety of human malignancies. The K-ras oncogene resides on chromosome 12p12, and encodes a 21-kD protein (p21ras) involved in the G-protein signal transduction pathway, modulating cellular proliferation and differentiation. The ras pathway is important in the transmission of growth-promoting signals from the cell surface receptors and affect the production and regulation of key proteins. Mutations of the K-Ras gene occur long before the formation of the actual cancer.

So far, researchers believe that the clinical significance of K-ras mutations is somewhat controversial. But a number of studies have shown lower median survival times in patients with mutation-positive tumors in gastrointestinal malignancies. As it turns out, K-ras mutations are one of the most common genetic abnormalities in colon, pancreatic cancers and bile duct carcinomas, detectable in greater than 75% of tumors. These cancers are extremely resistant to treatment.

In gynecological malignancies and endometrial carcinomas, K-ras mutations are noted in up to a third of cases. Studies have shown that in postmenopausal women with endometrial carcinomas, K-ras mutations appear to be an independent risk factor for adverse prognosis. Researchers believe that that the presence of K-ras mutations in endometrial hyperplasia specimens may identify a group of patients with a high probability for progression.

K-ras mutations are also associated with nearly 30% of non-small-cell lung cancer, the leading cause of cancer deaths in the United Sates. In limited stage adenocarcinomas, usually is seen peripherally in the lungs, the presence of K-ras mutation is independently associated with more aggressive disease and decreased patient survival.

"Finding a way to effectively treat K-Ras-mutated cancers would be a huge advance in solid tumor oncology, since these mutations are common in several incurable cancers," explained Jeffrey Engelman, MD, PhD, of the MGH Cancer Center, one of the report's co-lead authors. "Cancers with K-Ras mutations have been resistant to all targeted therapies to date, and it is exciting to learn that a combination of PI3K and MEK inhibitors, two families of drugs currently in clinical development, may be highly effective in these cancers."

The current study began with a focus on the PI3K signaling pathway, which is key to cell survival and known to control cellular motility and adhesion. PI3K mutations have caused tumor development in laboratory studies, but their role had not yet been studied in an animal model. The research team developed a transgenic mouse in which administration of the drug doxycycline induces the expression of cancer-associated PI3K mutations, leading to development of lung tumors.

Treatment of those animals with an investigational PI3K inhibitor did lead to rapid tumor regression. Since previous studies suggested that PI3K inhibition might also block K-Ras-induced tumor development, the investigators also tested the PI3K inhibitor in mice with K-Ras-stimulated tumors.

That treatment was ineffective, but since K-Ras also activates the MEK/ERK signaling pathway, the researchers treated the animals with an investigational MEK inhibitor and with a combination of both drugs. Treatment with the MEK inhibitor alone caused only a modest reduction in tumor size, but combined treatment with both agents caused the K-Ras-stimulated lung tumors to virtually disappear.

"For several years we have known that K-Ras activates two major pathways — the PI3K pathway and the MEK/MAPK pathway — and that these pathways have many redundant functions in tumor growth and survival," notes Lewis Cantley, PhD, of the BIDMC Cancer Center, one of the study's co-corresponding authors. Contley continues: "Inhibitors of both of these pathways are now in clinical trials, and in this paper we show that, while either agent alone has a minor effect on K-Ras-driven tumors in mice, combining inhibitors of both pathways eradicates these tumors with minimal toxicity."

Kwok-Kin Wong, MD, PhD, of Dana-Farber, also a co-corresponding author, adds, "The results of our study are truly remarkable and provide a strong and compelling scientific rationale to test this combination therapy in human phase 1 and 2 trials. This work would not have been possible without the highly productive collaboration between our laboratories at Mass. General, Beth Israel Deaconess and Dana-Farber."

Wong is an assistant professor of medicine at Harvard Medical School, where Engelman is also an assistant professor in medicine and Cantley is the Castle Professor of Medicine.

The researchers are hoping to advance towards clinical trials by testing combination therapy against other models of K-Ras-mutated cancer, including those that involve additional mutations in other tumor-associated genes, and to investigate whether K-Ras-associated tumors will become resistant to combination therapy, a problem that has plagued other targeted cancer therapies.

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