A Way Forward for Cancer Chemoprevention: Think Local

Abstract

As cells progress through carcinogenesis, the associated exponential expansion of genetic and molecular aberrations and resultant heterogeneity make therapeutic success increasingly unattainable. Therapeutic intervention at early stages of carcinogenesis that occurs within the primary organ and in the face of a lower burden of molecular aberrations, constitutes a basic tenet of cancer chemoprevention, and provides a situation that favors a greater degree of therapeutic efficacy compared with that of advanced cancer. A longstanding barrier to chemoprevention relates to the requirement for essentially no systemic toxicity, and the fact that when large numbers of people are treated, the emergence of systemic toxicity is almost universal. A rational means to address this in fact relates to a second basic tenet of the chemopreventive strategy: the focus of therapeutic intervention is to disrupt a process that is in essence localized to a single organ. Based upon this consideration, a strategy which is based upon local delivery of therapeutics to an at-risk organ will achieve therapeutic efficacy while avoiding systemic delivery and its associated toxicity. This article will review the rationale for undertaking such an approach, describe successful clinical achievements based on this strategy, describe ongoing efforts to expand the impact of this approach, and together will highlight the high impact that this approach has already had on the field as well as its extremely high potential for future impact. Cancer Prev Res; 10(1); 14-35. ©2016 AACR.

A Phase I Trial of Berberine in Chinese with Ulcerative Colitis

“…However, a central goal of cancer prevention agents is having little to no toxicity in the face of extended administration times. A consideration of these factors, and the fact that a given at-risk organ can be targeted through local drug delivery, is serving to drive the investigation of local delivery strategies in the field of cancer prevention (47). In the case of berberine, studies in rodents indicate that oral berberine is absorbed through the intestinal lining, undergoes rapid firstpass metabolism in the liver and has a systemic delivery of below 0.001% (48)(49)(50).…”

Acceptability of Localized Cancer Risk Reduction Interventions Among Individuals at Average or High Risk for Cancer

“…In fact, using topical agents in breast disease has been shown to deliver high concentrations in the breast with longer retention, decrease proliferation to the same degree as oral delivery, with low systemic exposure (36). There are currently 12 agents approved by the FDA for cancer risk reduction, although uptake of these agents is still not optimal (27). Pharmacologic studies of these agents suggest that small, lipophilic molecules with good dermal permeation are excellent candidates for topical application in cancer prevention (27,36).…”

“…There are currently 12 agents approved by the FDA for cancer risk reduction, although uptake of these agents is still not optimal (27). Pharmacologic studies of these agents suggest that small, lipophilic molecules with good dermal permeation are excellent candidates for topical application in cancer prevention (27,36). Moreover, direct application of active metabolites of preventive or therapeutic agents, bypassing metabolism and toxicity, has shown promising results.…”

“…As a result, recent research and clinical trials have focused on the development of chemopreventive agents and other risk-reducing interventions that are locally delivered to the primary organ of concern to reduce or possibly eliminate the systemic toxicities associated with oral administration. Examples include local transdermal therapy for the risk reduction of breast cancer, inhalation therapy for lung cancer, photodynamic light stimulation therapy for head and neck cancers, and a hormonal implant device for gynecologic cancers (27). While these local risk-reducing interventions hold promise for the effective prevention of certain cancers, it is essential that these efforts actually translate into increased acceptability among the general population, and in particular, those at high risk for specific cancers.…”

Mammographic Density as a Criterion of the Efficiency of Treatment of Benign Breast Disease and Reducing Risk of Breast Cancer

“…Например, в ряде исследований увеличение потребления овощей и фруктов, кальция и витамина D, низкожировая ди-ета снижали МГП [32]. К настоящему времени селек-тивные модуляторы эстрогеновых рецепторов тамок-сифен и ралоксифен официально одобрены FDA (США) для химиопрофилактики рака МЖ, близки к одобрению ингибиторы ароматазы [33]. В крупных интервенционных рандомизированных исследовани-ях доказано, что тамоксифен, ралоксифен и ингиби-торы ароматазы анастразол и экземестан при профи-лактическом применении существенно снижают риск развития рака МЖ [34].…”