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Originally published as JCO Early Release 10.1200/JCO.2008.18.3160 on September 29 2008 © 2008 American Society of Clinical Oncology.
Exploiting the Apoptotic Route for Cancer Treatment: A Single Hit Will Rarely Result in a Home Run
Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands 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.1 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.1,2 In addition, survivin was found to be upregulated after myocardial infarction in humans.2 Survivin is frequently overexpressed in most tumor types. In addition, its expression in several tumor types has been associated with poor prognosis in patients.3,4 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.5 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.1 In this issue of Journal of Clinical Oncology, Tolcher et al6 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/m2/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/m2/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,7,8 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 large-cell 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 receptor- or signal transduction–directed investigational agent and showed a response rate of just 3.2%.9 At the MTD, preliminary data with YM155 are available in therapy-naive patients with melanoma and patients with hormone-refractory prostate cancer who received prior taxane chemotherapy.10,11 In the first 26 patients with melanoma, there is one response at cycle 2 and one minor response at cycle 6.10 Results to date on 32 patients with prostate cancer showed two PSA responses at cycle 2 and cycle 6, respectively.11 In these phase II studies with YM155, no significant toxicity was seen, with no renal toxicity, although overall antitumor activity may be modest. Future insight into the number of patients who obtained stable disease might further increase interest. Given the favorable pharmacokinetics in the YM155 phase I study, with marked tissue distribution and a mean half-life of 26.3 hours at the MTD, it is realistic that more feasible, patient-friendly schedules can be used in the future. There are emerging data on other classes of survivin-targeting agents using antisense approach or vaccination.12-14 LY2181308, a 2`-O-methoxymethyl modified antisense oligonucleotide, which is an inhibitor of survivin mRNA, proved in a phase I study to induce survivin downregulation in tumors.12 No antitumor activity was observed. The results with other blockers targeting the IAP family are also becoming available. Preliminary data from phase I studies with antisense X-linked inhibitor of apoptosis (IAP) suggest some antitumor activity.15,16 Furthermore, important antiapoptotic regulators of the intrinsic apoptotic pathway belonging to the Bcl-2 family have been targeted. Most clinical data available for Bcl-2 antagonists are of antisense oligonucleotides targeting Bcl-2 mRNA.17-21 They show a contribution when combined with chemotherapy in chronic lymphocytic leukemia (CLL) and melanoma.18,20 In a phase III CLL trial, oblimersen, the antisense Bcl-2 added to chemotherapy, resulted in a higher CR rate (17% v 7%) with a longer response duration.20,21 YM155 and the antisense strategies do not actively inhibit the antiapoptotic proteins but indirectly inhibit their functionality via reduced mRNA expression of the target protein. A number of small molecule antagonists of IAP and antiapoptotic Bcl-2 family proteins have been designed that specifically block binding of IAP and Bcl-2 family proteins to their proapoptotic counterpart. Obatoclax, an antagonist of the Bcl-2 homology domain-3–binding groove of the Bcl-2 family of proteins has entered clinical trials,22 with hints of activity in hematologic malignancies. The use of ligands actively inducing apoptosis via the extrinsic pathway represents a completely different approach. A recombinant form (rhApo2L/TRAIL) of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and agonistic monoclonal antibodies against the TRAIL-DRs are now available. RhApo2L/TRAIL induces apoptosis after binding to the two membrane TRAIL-DRs, whereas the agonistic antibodies target either DR4 or DR5. In the rhApo2L/TRAIL phase I study, one PR was seen in a patient with a chondrosarcoma.23 In a phase Ib study evaluating the safety of rituximab in combination with RhApo2L/TRAIL in patients with NHL who had received rituximab in the past, three of five assessable patients responded.24 Six agonistic monoclonal antibodies against the DRs are currently in clinical trials.25-33 Three single-agent phase II studies with the anti-DR4 antibody mapatumumab showed that, among 40 patients with NHL,30 one CR and two PRs were observed, whereas no responses were observed in patients with NSCLC32 and colon cancer.33 In phase I studies with five DR5 targeting antibodies, one PR in NSCLC was observed.27 Studies of DR4 and DR5 antibodies combined with chemotherapy did not result in additional toxicity. All of these agents seem to be safe, but their single-agent activity, despite being the primary inducers of apoptosis, is low. Strikingly similar to the observations with YM155, beneficial effects are especially observed in NHL. The survivin-targeting agent YM155 might well be slightly more potent as a single agent compared with Bcl-2- or TRAIL-receptor–targeting therapies. The explanation could lie in the fact, as Altieri1 stresses in his excellent review on survivin, that it is actually a nodal protein linking multiple pathways of cellular homeostasis. Apart from being a regulator of apoptosis, it is a regulator of cell division and nonapoptotic cell death, a stress response factor, and a promotor of tumor-associated angiogenesis. Fortunately, several apoptosis-inducing targeted agents have shown some single-agent activity in early clinical trials. However, all data seem to suggest that their future role lies in combination therapy. It seems unrealistic that hitting just one component of a pathway in which so many team-playing proteins are involved (often with redundant activities) will be effective. One can envision that drug combinations targeting several components within the apoptotic pathways or other nonapototic pathways would be more effective. Until now, these agents are primarily being tested in combination with chemotherapy. The question remains whether these agents should be highly specific to an individual protein in a pathway or target a nodal protein within several pathways for optimal antitumor efficacy. The fact that survivin is a nodal protein linking multiple pathways of cellular homeostasis makes YM155 an attractive drug to combine with other agents. For combination trials with YM155, the toxicity profile observed in the phase I trial—especially the renal toxicity—deserves close attention. In addition, one must take into account that tumor response can occur late in treatment. Collection of blood and tissue samples for biomarkers of different layers of gene regulation in future studies would be of major help gaining insight into the tangle of apoptotic signaling pathway interactions within the individual cancer patient. Potentially, this insight can guide optimal personalized combination therapy and increase the chance with rationally chosen multiple hits for a home run. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Elisabeth G.E. de Vries, Novartis, Human Genome Sciences Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Elisabeth G.E. de Vries, Steven de Jong Manuscript writing: Elisabeth G.E. de Vries, Steven de Jong Final approval of manuscript: Elisabeth G.E. de Vries, Steven de Jong ACKNOWLEDGMENTS Supported by Grants No. RUG2005-3361, 2005-3365, 2007-3719 and VU2006-3567 from the Dutch Cancer Society. NOTES published online ahead of print atwww.jco.org on October 13, 2008 REFERENCES 1. Altieri DC: Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8:61-70, 2008[CrossRef][Medline] 2. Santini D, Abbate A, Scarpa S, et al: Surviving acute myocardial infarction: Survivin expression in viable cardiomyocytes after infarction. J Clin Pathol 57:1321-1324, 2004 3. Schlette EJ, Medeiros LJ, Goy A, et al: Survivin expression predicts poorer prognosis in anaplastic large-cell lymphoma. J Clin Oncol 22:1682-1688, 2004 4. Chakravarti A, Noll E, Black PM, et al: Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol 20:1063-1068, 2002 5. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004 6. Tolcher AW, Mita A, Lewis LD, et al: Phase I and pharmacokinetic study of YM155, a small molecule inhibitor of survivin. J Clin Oncol doi:10.1200/JCO.2008.17.2064 [epub ahead of print on September 29, 2008] 7. 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O’Brien S, Moore JO, Boyd TE, et al: Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 25:1114-1120, 2007 21. Rai KR, Moore J, Wu J, Novick SC, et al: Effect of the addition of oblimersen (Bcl-2 antisense) to fludarabine/cyclophosphamide for relapsed/refractory chronic lymphocytic leukemia (CLL) on survival in patients who achieve CR/nPR: Five-year follow-up from a randomized phase III study. J Clin Oncol 26:374s, 2008 (suppl; abstr 7008)[CrossRef] 22. Reed JC: Bcl-2-family proteins and hematologic malignancies: History and future prospects. Blood 111:3322-3330, 2008 23. Herbst RS, Mendolson DS, Ebbinghaus S, et al: A phase I safety and pharmacokinetic (PK) study of recombinant Apo2L/TRAIL, an apoptosis-inducing protein in patients with advanced cancer. J Clin Oncol 24:124s, 2006 (suppl; abstr 3013) 24. 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Saleh MN, Percent I, Wood TE, et al: A phase I study of CS-1008 (humanized monoclonal antibody targeting death receptor 5 or DR5), administered weekly to patients with advanced solid tumors or lymphomas. J Clin Oncol 26:141s, 2008 (suppl; abstr 3537) 29. Sharma S, De Vries EG, Infante JR, et al: Phase I trial of LBY135, a monoclonal antibody agonist to DR5, alone and in combination with capecitabine in advanced solid tumors. J Clin Oncol 25:157s, 2008 (suppl; abstr 3538) 30. Tolcher AW, Mita M, Meropol NJ, et al: Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol 25:1390-1395, 2007 31. Younes A, Vose J, Zelenetz AD, et al: Results of a phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/refractory non-Hodgkin's lymphoma (NHL). Blood 106:146a, 2005 (suppl; abstr 489) 32. Greco FA, Bonomi P, Crawford J, et al: Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer. Lung Cancer 10.1016/j.lungcan.2007.12.011 [epub ahead of print on February 5, 2008][CrossRef][Medline] 33. Kanzler S, Trarbach T, Heinemann V, et al: Results of a phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed or refractory colorectal cancer (CRC). Presented at the 13th European Cancer Conference, October 30-November 3, 2005, Paris, France (suppl; abstr 630)
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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