Background-Standard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation.

There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphate-activated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics.

Colon cancer is treated adjuvantly with 5-flourouracil (5-FU) and oxaliplatin, most commonly as part of the FOLFOX regimen, which has less toxicity than the older regimen FLOX (bolus 5-FU and oxaliplatin) that has fallen out of favor. For patients who cannot tolerate oxaliplatin, 5-FU can be given as a single agent. Patients with metastatic disease may be treated with a number of regimens, including FOLFOX and FOLFIRI; however, the environment is a not a monotonous vanilla and chocolate FOLFOX and FOLFIRI. Cytotoxic agents, sequentially or in combination, are frequently combined with biologic agents to improve response in metastatic disease. Clinical investigators have focused considerable attention on how best to apply all the agents active in metastatic colon cancer, a practice in evolution. In this article, we highlight important, informative research regarding cytotoxic chemotherapy for colon cancer. We also recognize the contribution made by skilled surgeons, interventional radiologists, and radiation oncologists who will push the envelope and as well, the pharmacogenomic and molecular markers that help us to understand mechanisms of disease, predict toxicity, and refine our therapy.

No abstract