Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes

Abstract

Personalized cancer medicine is becoming increasingly important in colorectal cancer treatment. Especially for targeted therapies, large variations between individual treatment responses exist. Predicting therapy response is of utmost significance, as it prevents overtreatment and adverse effects in patients. For EGFRtargeted therapy, many mechanisms of resistance have been uncovered, for example, mutations in KRAS and BRAF, and upregulation of alternative receptors. Currently, routine testing for all known modifiers of response is unpractical, and as a result, decision-making for anti-EGFR therapy is still largely based on assessing the mutation status of an individual gene (KRAS). Recently, comprehensive classifications of colorectal cancer have been presented that integrate many of the (epi-)genetic and microenvironmental factors that contribute to colorectal cancer heterogeneity. These classification systems are not only of prognostic value but also predict therapy efficacy, including the response to anti-EGFR agents. Therefore, molecular subtypebased stratification to guide therapeutic decisions is a promising new strategy that might overcome the shortcomings of single gene testing in colorectal cancer as well as in other malignancies. Furthermore, the development of new agents in a disease subtype-specific fashion has the potential to transform drug-discovery studies and generate novel, more effective therapies. Cancer Res; 75(2); 245-9. Ó2014 AACR.

Prediagnosis Sleep Duration, Napping, and Mortality Among Colorectal Cancer Survivors in a Large US Cohort

“…27 The different findings for CRC risk and mortality in the same study could be potentially explained by several factors: First, it has been reported that there are several subtypes of CRC with different etiology, prognosis, and response to treatments. 28,29 For example, it has been noted that inflammation-associated CRC has a distinct molecular feature and poor outcomes. 30 It is possible that the association between sleep and CRC varies by subtype, and if sleep deficiency has a particularly strong link with those subtypes with poor prognosis, such as the inflammation subtype, then it would be reasonable to expect that sleep duration may have a smaller impact on overall CRC risk but a larger effect on CRC mortality.…”

Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells

“…While the molecular mechanisms by which CRC begins and then progresses to metastatic disease are better understood relative to some other cancer types (Tomasetti et al 2014;Linnekamp et al 2015), current treatments such as with the first-line chemotherapeutic drug 5-fluorouracil (5-FU) are largely ineffective once the tumor becomes invasive, metastatic and/or chemo-resistant (Paldino et al 2014). Hence, preventing CRC initiation, progression and recurrence and defining bona fide targets for effective therapies are paramount for reducing CRC-related mortality.…”

Expression and clinical significance of Sirt1 in colorectal cancer

“…In order to identify possible gene target therapies and individualized treatments, various studies have focused on genes associated with the pathogenesis of colorectal cancer and their mechanisms. Previous studies have employed various methods to explore potential markers for the early diagnosis and prognosis of colorectal cancer; however, at present, its primary cause is unknown, and therefore further research is required (9).…”