Targeted therapies and the consequent adoption of “personalized” oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity “broad-spectrum” therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested; many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to help us address disease relapse, which is a substantial and longstanding problem, so a proposed agenda for future research is offered.

One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed “senescence,” can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells’ heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy.

We previously demonstrated in prostate cancer cells that a phytochemical-perillyl alcohol-and the mechanistic target of rapamycin (mTOR) inhibitor rapamycin rapidly attenuated telomerase activity. Protein levels of the telomerase catalytic subunit reverse transcriptase (hTERT) were diminished in the absence of an effect on hTERT mRNA, supporting an effect on 4E-BP1 phosphorylation and reduced initiation of protein translation. The decline in hTERT protein did not coincide wholly, however, with loss of telomerase activity suggesting a further level of regulation. We hypothesized that a hTERT-mTOR-S6K (S6 kinase)-Hsp90 (Heat shock protein 90)-Akt complex previously detected in activated NK cells was present in DU145 prostate cancer cells. Furthermore, we postulated that both perillyl alcohol and rapamycin disrupted this complex to control telomerase activity post-translationally. Antibodies directed against either RAPTOR, a binding partner of mTOR, or mTOR itself co-immunoprecipitated Hsp90, hTERT, and S6K confirming a similar TERT complex in prostate cancer cells. Perillyl alcohol or rapamycin caused rapid dissociation of the captured hTERT-mTOR-RAPTOR complex, establishing an additional mechanism by which these agents decrease telomerase activity. These findings provide convincing evidence for mTOR-mediated regulation of hTERT in DU145 cells.

Telomeres are stretches of repeated DNA sequences located at the ends of chromosomes that are necessary to prevent loss of gene-coding DNA regions during replication. Telomerase - the enzyme responsible for immortalising cancer cells through the addition of telomeric repeats - is active in ~90% of human cancers. Telomerase activity is inhibited by various phytochemicals such as isoprenoids, genistein, curcumin, epigallocatechin-3-gallate, resveratrol and others. Human TERT (telomerase reverse transcriptase - the rate-limiting component of telomerase), heat shock protein 90, Akt, p70 S6 kinase (S6K) and mammalian target of rapamycin (mTOR) form a physical and functional complex with one another. The inclusion of Akt, mTOR and S6K in the TERT complex is compelling evidence to support mTOR-mediated control of telomerase activity. This review will define the role of mTOR, the master regulator of protein translation, in telomerase regulation and provide additional insights into the numerous ways in which telomerase activity is hindered by phytochemicals.