sirolimus and tipifarnib

Colorectal cancer is the second leading cause of cancer death in Switzerland. The nihilism that dominated the treatment of these patients for decades has been replaced by a measure of enthusiasm, given recent therapeutic advances. New anticancer drugs such as irinotecan and oxaliplatin have changed the standard chemotherapy treatment of metastatic colorectal cancer. However, the real hype has come from molecular targeted therapy. Identification of cellular processes characteristic of colon cancer has permitted therapeutic targeting with favorable therapeutic index. Inhibition of the epidermal growth factor receptor in the clinic has provided proof of principle that interruption of signal transduction cascades in patients has therapeutic potential. Angiogenesis, especially the vascular endothelial growth factor pathway, has been proven to be another highly successful molecular target. In this article, we will review molecular targets, which are under active clinical investigation in colon cancer.

Topics: Angiogenesis Inhibitors; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Camptothecin; Cetuximab; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Colonic Neoplasms; Drug Delivery Systems; ErbB Receptors; Gefitinib; Humans; Imatinib Mesylate; Indoles; Irinotecan; Organoplatinum Compounds; Oxaliplatin; Phthalazines; Piperazines; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Quinolones; Receptors, Platelet-Derived Growth Factor; Receptors, Somatomedin; Signal Transduction; Sirolimus; Sunitinib

Signaling pathway stimulation by activating mutations of oncogenes occurs in most melanomas and can provide excellent targets for therapy, but the short-term therapeutic success is limited by intrinsic and acquired resistance. The mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT/mTOR pathways are activated in most cutaneous melanomas. The purpose of this trial was to prospectively evaluate 2 molecularly targeted drug combinations in patients with untreated metastatic melanoma.. This randomized phase II study enrolled patients between May 2008 and November 2009 with nonocular melanoma, no prior systemic chemotherapy, and no history of brain metastasis. Arm A received oral sorafenib 200 mg twice daily plus i.v. temsirolimus 25 mg weekly; and arm B received oral sorafenib 400 mg every morning, 200 mg every night daily plus oral tipifarnib 100 mg twice daily, 3 weeks of every 4. The primary objectives were to evaluate progression-free survival (PFS), objective response rate, and toxicity for the 2 regimens.. On arm A (63 evaluable patients), the median PFS was 2.1 months and median overall survival (OS) was 7 months. Three patients achieved partial response (PR). Thirty-nine evaluable patients were accrued to arm B, which closed after first-stage accrual; the median PFS was 1.8 months and OS was 7 months, with 1 patient achieving PR.. The combinations of molecularly targeted agents tested did not show sufficient activity to justify further use. Newer agents and improved patient selection by characterization of the molecular targets in individual tumors show great promise and should be incorporated into future studies, along with appropriate laboratory correlates.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Pyridines; Quinolones; Sirolimus; Sorafenib; Survival Analysis; Treatment Outcome

Small molecules are attractive agents for the treatment of leukemia. We found that a combination of a farnesyltransferase inhibitor, tipifarnib, and an mTOR inhibitor, rapamycin, synergistically inhibited the growth of myeloid leukemia cell lines and primary leukemia cells by inducing apoptosis and cell-cycle blockage. The combined agents reduced the level of phospho-ERK1/2, suggesting that they altered the network of signaling pathways. They also showed synergistic effects in tipifarnib-resistant K562/RR cells. The results support the utility of this combination as a potential therapy for leukemia. The combination might also be effective in overcoming resistance to tipifarnib.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cell Cycle; Cell Proliferation; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Leukemia; Quinolones; Signal Transduction; Sirolimus; Tumor Cells, Cultured