Oral drugs in the treatment of metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common forms of cancer, with an estimated 1.36 million new cases and almost 700,000 deaths annually. Approximately 21% of patients with CRC have metastatic disease at diagnosis.

Neutral evolution of drug resistant colorectal cancer cell populations is independent of their KRAS status.

Emergence of tumor resistance to an anti-cancer therapy directed against a putative target raises several questions including: (1) do mutations in the target/pathway confer resistance? (2) Are these mutations pre-existing? (3) What is the relative fitness of cells with/without the mutation? We addressed these questions in patients with metastatic colorectal cancer (mCRC). We conducted an exhaustive review of published data to establish a median doubling time for CRCs and stained a cohort of CRCs to document mitotic indices. We analyzed published data and our own data to calculate rates of growth (g) and regression (d, decay) of tumors in patients with CRC correlating these results with the detection of circulating MT-KRAS DNA.

A phase I, dose-escalation study of the multitargeted receptor tyrosine kinase inhibitor, golvatinib, in patients with advanced solid tumors.

Purpose: Receptor tyrosine kinases c-Met and Ron transduce signals regulating cell migration and matrix invasion. This phase I dose-escalation trial tested golvatinib, a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family plus c-Kit and Ron.

Experimental Design: Patients with advanced solid tumors received golvatinib orally, once daily, continuously.

Cancer therapeutics: Targeting the apoptotic pathway.

Apoptosis, a physiological process of programmed cell death, is disrupted in various malignancies. It has been exploited as an anti-cancer strategy traditionally by inducing DNA damage with chemotherapy and radiotherapy. With an increased understanding of the intrinsic and extrinsic pathways of apoptosis in recent years, novel approaches of targeting the apoptotic pathways have been tested in pre-clinical and clinical models.

Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats.

Cisplatin is an anticancer agent marred by nephrotoxicity; however, limiting this adverse effect may allow the use of higher doses to improve its efficacy. Cilastatin, a small molecule inhibitor of renal dehydropeptidase I, prevents proximal tubular cells from undergoing cisplatin-induced apoptosis in vitro. Here, we explored the in vivo relevance of these findings and the specificity of protection for kidney cells in cisplatin-treated rats.

Outcomes of patients with metastatic melanoma treated with molecularly targeted agents in phase I clinical trials.

Introduction: First-line treatment options utilizing chemotherapy and cytokine-based treatments for patients with metastatic melanoma (MM) are unsatisfactory. We analyzed the clinical outcomes of patients with MM treated in phase I trials of novel agents. We hypothesized that patients included in phase I clinical trials did not have worse outcomes than with the chemotherapy and cytokine-based first-line treatment.