The mTOR (mammalian target of rapamycin) pathway is activated in many cancers and has become an exciting new target for inhibition with agents, known as mTOR inhibitors, now showing promise in clinical trials in different tumors, according to Robert A. Figlin, MD, Arthur and Rosalie Kaplan Professor of Medical Oncology and Chairman of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center, Duarte, California. Dr. Figlin summarized the National Comprehensive Cancer Network (NCCN) Task Force report on mTOR inhibitors.
mTOR controls cell growth and angiogenesis through a series of mechanisms that integrate signaling from nutrients and other growth-promoting pathways. Activation of mTOR (downstream of the PI3K/Akt pathway) results in protein synthesis, proliferation of tumor cells, angiogenesis, and nutrient uptake. These consequences can be countered by mTOR inhibition, he explained.
Inhibition of mTOR affects not only the cancer cell directly but also the endothelial cell that accompanies the cancer cell; therefore, the impact on tumor cell growth and angiogenesis could be substantial.
But since the signaling pathway is so complex, it is unlikely that mTOR inhibition alone will be sufficient to stop cancer cell growth for most types of cancer. “The mTOR pathway deserves understanding and research because it will be integral in combined targeted approaches involving other agents,” Dr. Figlin predicted.
The backbone of mTOR inhibitors is rapamycin (sirolimus, Rapamune). Analogs now in clinical or investigational use include temsirolimus (Torisel), everolimus (RAD001), and deforolimus (AP23573). These agents are administered intravenously (temsirolimus), orally (everolimus), or by both routes (deforolimus) and differ in antitumor activity, pharmacodynamics, and pharmacokinetics. Their major side effects include cytopenia, rash, and stomatitis, as well as the more unusual (for targeted agents) effects of hyperlipidemia and hyperglycemia.
There is a strong rationale for using mTOR inhibitors in renal cell carcinoma (RCC). The von Hippel-Lindau (VHL) abnormality seen in RCC sensitizes the cancer to mTOR inhibition, which limits tumor growth and angiogenesis.
A global trial of temsirolimus in 626 poor-prognosis metastatic RCC patients (Hudes G et al. N Engl J Med 2007;356:2271–2281) demonstrated not only a doubling in progression-free survival but a relative survival benefit of 49% for temsirolimus monotherapy versus interferon-alfa (the standard of care), extending survival to nearly 11 months. Most subsets (including histologic types) benefited from the treatment.
“This was the first phase III trial in RCC showing an overall benefit of an investigational agent versus a control,” Dr. Figlin noted. The approach is to treat patients until disease progression, if they are tolerating the drug. Main side effects in the trial were asthenia, nausea, rash, and anemia, with complications of glucose metabolism and lipid metabolism occurring in over a third of patients. Clinicians should therefore obtain baseline lipid and glucose profiles and monitor them regularly during treatment.
The NCCN guidelines now recommended temsirolimus firstline in poor-risk patients with clear cell and non-clear cell histologies. Although it is also recommended as secondline treatment among RCC patients who failed to respond to cytokines or the vascular endothelial growth factor (VEGF)/tyrosine kinase inhibitors sunitinib (Sutent) and sorafenib (Nexavar), data are still limited. “What we need to do is provide answers to second-line therapy…particularly after failure to VEGF receptor or ligand inhibition,” Dr. Figlin maintained. There is some suggestion that patients refractory to VEGF inhibitors may benefit from mTOR inhibitors, according to emerging data from a 362-patient phase III study of everolimus that showed an improvement in progression-free survival. Details of these results were not known at the time of presentation but are expected to be reported at the American Society of Clinical Oncology (ASCO)’s annual meeting in 2008.
“After ASCO, the NCCN panel on RCC will review this study and revisit our guidelines on the use of the mTOR inhibitors,” Dr. Figlin said.
In neuroendocrine tumors, use of mTOR inhibitors is backed by a solid scientific rationale because of the involvement of the tuberous sclerosis complex, a regulator of mTOR. However, clinical evidence of their activity in these tumors currently is less robust than it is in RCC. Results are expected this year from phase III studies of mTOR inhibitors in neuroendocrine cancer, and clinical trials of these agents in cancers of the liver, colon, gallbladder, and pancreas are ongoing, Dr. Figlin asserted.
There is an indication that simultaneous targeting of HER2 (human epidermal growth factor 2) signaling at two levels with trastuzumab (Herceptin) and an mTOR inhibitor may be beneficial in selected cases. In HER2-positive breast cancer cell lines, trastuzumab and rapamycin have additive, and possibly synergistic, activity. Pathway synergy will be important in trial design. “I’d like to see patients who are HER2-positive, [estrogen receptor]-positive, and…known PTEN status receive combinations of trastuzumab and mTOR inhibition,” Dr. Figlin remarked.
Pathway interactions are also crucial for mTOR in lung cancer. Combined inhibition of the epidermal growth factor receptor (EGFR) and mTOR can downregulate the activity of Akt, which is frequently activated in lung cancer and associated with poor prognosis. Although mTOR inhibitors have limited single-agent activity in this tumor, they may improve the efficacy of the EGFR tyrosine kinase inhibitors, he said.
In an ongoing phase II study, Kris and colleagues combined everolimus with gefitinib (Iressa) to achieve a 1-year survival rate of 68% in chemotherapy-naive patients; median survival had not yet been achieved at the time of reporting (J Clin Oncol 2007;25[18S]:7575). In previously treated patients, 1-year survival was 36% and median survival was 12 months.
“This is hypothesis-generating only, but it suggests we might select a patient population in whom to test these combinations,” Dr. Figlin commented.
Inhibition of the mTOR pathway may also be highly relevant in prostate cancer. Loss of the tumor suppressor gene PTEN occurs in 30%–60% of prostate cancers and leads to activation of the PI3K/Akt pathway and mTOR. Loss of PTEN correlates with a high Gleason score, advanced stage, and androgen independence. This pathway provides a target in androgen-resistant patients, Dr. Figlin pointed out.
There are a number of ongoing mTOR-based trials in prostate cancer evaluating temsirolimus, everolimus, rapamycin, and deforolimus in a variety of combinations. “My bias is that we have to recognize that most patients will not benefit from mTOR inhibition monotherapy, but will need combinations with other agents, although some tumors may be exceptions to this,” he said. “It’s rare that mTOR inhibition by itself is sufficient to turn off cancer cell growth.”
Loss of PTEN occurs in up to 80% of endometrial cancer, resulting in mTOR activation and increasing angiogenesis and tumor progression. In a phase II trial of temsirolimus in untreated recurrent or metastatic endometrial cancer, remissions were achieved in 26% of patients and disease stabilization in 63% (Oza AM et al. J Clin Oncol 2006;24[18S]:3003). In a phase II study of deforolimus in previously treated recurrent endometrial cancer, 33% of patients derived clinical benefit (Columbo N et al. J Clin Oncol 2007;25[18S]:5516).
“This suggests that endometrial cancer is an important target of these agents,” Dr. Figlin concluded. This is good news, he noted, “because we don’t have much else to offer patients after first-line cytotoxic chemotherapy.” Future studies will evaluate mTOR inhibitors in combination with paclitaxel and carboplatin.
In ovarian cancer, the importance of VEGF inhibition to control ascites brings mTOR modulation into light. With the angiogenic activity of mTOR inhibitors, “it would not be a surprise to combine mTOR inhibition with cytotoxic therapy in this disease,” he commented.
In conclusion, Dr. Figlin emphasized that the most definitive activity has been observed in kidney cancer, and additional studies to be presented at ASCO will help define the role of these agents in this disease. But the value of mTOR inhibition is not limited to RCC. “There are a myriad of diseases where mTOR is important, and these inhibitors may be effective,” Dr. Figlin added.