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The Rapalogs: New Class of Therapy for Women with Endometrial Cancer
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports that he receives research funding from Novartis, which makes an mTOR inhibitor (everolimus).
Synopsis: Temsirolimus, an inhibitor of mTOR, demonstrates activity in patients with advanced or recurrent endometrial cancer. Its clinical activity appears to be strongly influenced by prior chemotherapy exposure but not by histology or aberration in the PI3K pathway.
Source: Oza AM, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: A trial of the NCIC Clinical Trials Group. J Clin Oncol 2011;29:3278-3285.
Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that is commonly mutated in endometrial and other cancers. Loss of PTEN causes deregulation of the phosphatidylinositol-3 kinase/serine-threonine kinase/ mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway, and provides a selective survival advantage to cancer cells via angiogenesis augmentation, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin, inhibits mTOR and was evaluated as a single agent (25 mg weekly intravenously, 4-week cycles) in sequential Phase 2 studies of women with recurrent or metastatic chemotherapy-naïve (Group A) or chemotherapy-treated (Group B) endometrial cancer. In Group A, 33 patients received a median of four cycles (range: 1 to 23 cycles). Of the 29 patients who were evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months and 9.7 months, respectively. Only five patients (18%) had progressive disease. In Group B, 27 patients received a median of three cycles (range: 1 to 6 cycles), and of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months and 3.7 months, respectively. PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome. mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer, which is higher in chemotherapy-naïve than in chemotherapy-treated patients and is independent of PTEN status.
It is well-appreciated in the obstetrics and gynecology community that endometrial cancer is a gynecological malignancy increasing in incidence. More than one in five new cases of the disease will prove fatal — a proportion that is increasing with the epidemic of obesity. Adipose tissue produces potent extrinsic mediators for cellular growth, leading to an increased likelihood for events promoting carcinogenesis.1 One of the most interesting and prevalent events is activation of the PI3K pathway, which is "turned on" by a number of growth factors, including epidermal growth factor, fibroblast growth factor, and insulin growth factor.2 A principal regulator of this pathway is PTEN, a tumor suppressor gene. When this gene is knocked out in mice, endometrial hyperplasia forms, demonstrating the important role this gene has on the checks and balance of cellular growth in the uterus. In humans, PTEN can become mutated or down-regulated by other genes (such as src), losing its ability to suppress signaling under ligand stimulation. In addition, the pathway can be activated by gain-of-function mutations in PI3K itself or in downstream effectors, such as Akt, even if PTEN is functioning normally.3 One downstream effector of the PI3K pathway is mTOR (mammalian target of rapamycin).
In recent years, several compounds have been developed to inhibit activation of mTOR. As a class, these agents are called "rapalogs," as they are derivatives of rapamycin, an immunosuppressive agent used in transplant patients. Several rapalogs are now available and are entering the clinical sphere of endometrial cancer therapy.4
Temsirolimus, the focus of this study, is one of the first to report activity as a single agent in women with measurable endometrial cancer. The reason this study is noteworthy is that it describes the clinical activity of an agent that is specifically targeted to a protein, which is believed to drive the cancer process. This is very distinct from chemotherapy, which generally exerts its effect by inducing indiscriminant cell death of rapidly dividing cells (cancer and otherwise). As such, the side-effect profile of these new targeted medicines is much different than chemotherapy and could provide new avenues of therapy for this disease. The fact that prior chemotherapy had such a profound effect on the clinical response to temsirolimus suggests that other pathways ("workarounds") may be activated as disease progresses. Indeed, it has been recognized that a parallel pathway (the ras/raf/MEK) can drive carcinogenesis even with PI3K pathway silencing. Fortunately, several available compounds target the workaround pathway, leading to new trial designs where one or both pathways are targeted in drug combinations or as sequential therapy. The important tenet of these studies is that pathway activation can be measured in tumor prospectively, allowing specific treatment allocation based on this tumor profiling. It is hoped that such a strategy will optimize individual patient care; an important goal as there currently are no FDA-approved non-hormonal agents for this endometrial cancer.