Exploiting the Apoptotic Route for Cancer Treatment: A Single Hit Will Rarely Result in a Home Run
Authors: Elisabeth G.E. de Vries, Steven de Jong
Journal: Journal of Clinical Oncology (2008)

Chemotherapy and radiotherapy are mainstays of cancer treatment, primarily by affecting dividing cells. In addition to these treatments, the development of drugs targeting specific proteins, which interfere in signaling pathways, has advanced tremendously. Aberrant apoptosis is a hallmark of cancer cells, which can be executed through an intrinsic, mitochondria-dependent pathway, and an extrinsic, death receptor (DR) –dependent, pathway. These pathways converge at the level of downstream effector caspases. The intrinsic pathway can be initiated by chemotherapy or radiotherapy, and the extrinsic pathway can be initiated by ligand-induced activation of DRs on the cell membrane. To evade apoptosis, tumor cells often show aberrations in genes and proteins involved in the apoptotic pathways. Consequently, there is obvious interest in several drugs currently in clinical trials that specifically inhibit antiapoptotic signaling or actively induce apoptosis. Survivin is a member of the family of inhibitors of apoptosis (IAPs), which are inhibitors of caspase-3, caspase-7, and caspase-9 activation; these therefore, negatively regulate apoptosis via the intrinsic as well as the extrinsic pathway. Survivin is expressed in fetal tissue and has been considered to be rarely expressed in adult tissues. However, survivin was recently found to be expressed in adult tissues such as hematopoietic CD34 cells, thymus, gastric mucosa and colonic crypts, testis, endometrium, placenta, hair follicle, and renal tubular cells. In addition, survivin was found to be upregulated after myocardial infarction in humans. Survivin is frequently overexpressed in most tumor types. In addition, its expression in several tumor types has been associated with poor prognosis in patients. For example, in patients with node-negative tamoxifen-treated breast cancer, survivin has been shown to be one of the 16 cancer-related genes which, when studied together with five reference genes, can be used to score and stratify patients at risk of recurrence. Furthermore, survivin is considered to confer resistance to chemotherapy and radiotherapy. These characteristics make survivin an interesting, although unusual, target. As such, survivin is neither an enzyme nor a receptor, but a protein that antagonizes apoptosis independently of caspase activation by binding to other adaptor or cofactor molecules. In this issue of Journal of Clinical Oncology, Tolcher et al present the first full report of an interesting phase I study in the class of survivin-targeting drugs. The small molecular suppressor of survivin expression, YM155, was administered intravenously continuously during 7 days, every 3 weeks. Toxicity consisted of stomatitis, pyrexia, and nausea. At the highest dose step of 6.0 mg/m/d, reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting. The maximum tolerated dose (MTD) was found to be 4.8 mg/m/d. The stomatitis might be due to survivin expression in the GI crypt cells. Renal toxicity after YM155 seen both in the animal model and in patients is likely the consequence of survivin overexpression in renal tubular cells, where it plausibly plays a functional role. Despite overexpression of survivin in CD34 cells, bone marrow depression was not frequently observed. The authors rightly observed provocative antitumor activity. The 41 patients were all extensively pretreated. Three patients with non-Hodgkin’s lymphoma (NHL) obtained a response consisting of one complete response (CR) at cycle 6; one partial response (PR) in follicular largecell lymphoma after 16 cycles, which lasted 8 months; and one PR after cycle 8, which is ongoing for more than 2 years. Two of the patients with prostate cancer had a prostate-specific antigen (PSA) response after cycles 2 and 9, respectively, and one minor response occurred in non–small-cell lung cancer (NSCLC). All but one response was at the MTD or higher dose. Strikingly, several of the responses took a long treatment period to occur. That there were responders among patients with NHL and PSA responses in patients with prostate cancer might have slightly favored the response rate results. A response while a patient is receiving an antiapoptotic agent is not unusual for NHL. In addition, PSA is still a relatively weak measure of response. Given the nature of phase I studies, statistical comparisons are impossible for tumor response results. However, a 12.1% response rate in this phase I study with YM155 seems robust compared with other studies. In an analysis of 460 phase I oncology trials involving 11,935 participants, 1,347 received single-agent treatment with a receptoror signal transduction– directed investigational agent and showed a response rate of just 3.2%. At the MTD, preliminary data with YM155 are available in therapy-naive patients with melanoma and patients with hormonerefractory prostate cancer who received prior taxane chemotherapy. In the first 26 patients with melanoma, there is one response at cycle 2 and one minor response at cycle 6. Results to date on 32 patients with prostate cancer showed two PSA responses at cycle 2 and cycle 6, respectively. In these phase II studies with YM155, no significant toxicity was seen, with no renal toxicity, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 32 NOVEMBER 1