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Originally published as JCO Early Release 10.1200/JCO.2005.10.963 on February 7 2005 © 2005 American Society of Clinical Oncology.
Indifferently Pursued or Unowned Drugs: Who Should Lead Where Companies Do Not Tread?Greenebaum Cancer Center, University of Maryland, Baltimore, MD The essence of a successful drug development program for cancer is the demonstration of safety and efficacy (defined as clinical benefit) in the intended population. As others have observed, molecularly targeted agents having potential noncytotoxic end points have, for the most part, proceeded through fairly standard decision-making algorithms, in which responses early in an agent's development serve as an important signal of potential clinical benefit and form the basis for subsequent development.1 With even a hint of such responses, it is possible to map out a strategy that may lead to expeditious regulatory approval. Recent good examples of agents of this type vigorously pursued by industry include bortezomib in multiple myeloma2 and gefitinib in lung cancer.3 In the case of agents that modulate tumor-cell resistance to chemotherapy or biologics that act in concert with cytotoxic agents, such as cetuximab4 and bevacizumab,5 more complicated strategies, including randomized approaches in precisely defined study populations, are necessary and appropriate. Such studies clearly benefit from industry-based organizational drive and expertise for their expeditious design and completion. Pharmaceutical companies tend to want such post–phase I programs to proceed expeditiously and generally demonstrate a lessening of ardor if the plan for definitive registrational trials lasts beyond a 3- to 5-year time frame; that latter number would be considered generous by many. The problem is that this time table ill serves the cause of agents that have a development strategy that arises from academic investigators working with hypothesis-directed, rather than market-oriented, goals. The compounds studied may not actually belong to a particular company, or the relevant company may not see the basis for facile regulatory approval, even with interesting clinical results from such small investigator-driven trials. Therefore, are we risking the loss of useful opportunities? How can such agents, which might lie at the fringe or indeed outside the envelope of corporate sponsorship, be usefully pursued? Is all oncology drug discovery and development to be driven by a corporate timetable, potentially not benefiting from informed maturation of a drug's intellectual and practical basis for use that might come from study in academically oriented laboratory programs and their derivative clinical trials? In this issue, Kortmansky et al6 report a phase I trial of escalating doses of fluorouracil (FU) in conjunction with the protein kinase antagonist 7-hydroxystaurosporine (UCN-01; NSC 638850). The rationale for this study came from prior laboratory investigations from this group,7 which demonstrated that UCN-01 caused downregulation of thymidylate synthase (TS), potentially as the result of UCN-01–induced decline in the activity of the E2F transcription factor.8 Because the level of TS expression has been linked by a number of (but not all) prior studies to the ultimate efficacy of FU-based therapies, with low levels of TS correlating with increased evidence of drug efficacy,9 a molecular basis for favorable modulation of FU efficacy by UCN-01 could be imagined. The results of the phase I study are encouraging. The study by Kortmansky et al6 clearly shows that a full dose of 24-hour infusional FU can be administered with the previously identified10 maximum-tolerated dose of UCN-01 without exacerbating either FU-related toxicities or the expected toxicities of UCN-01. Although no formal responses were observed in this generally heavily pretreated population, interesting oncophenomena occurred, including the perception of stable disease beyond 2 months in approximately one quarter of the assessable patients, which mirrors a prior suggestion of disease stabilization in a fraction of refractory lung cancer patients treated with UCN-01 and carboplatin.11 An effort in Kortmansky et al's study to discern modulation of TS mRNA in peripheral-blood mononuclear cells was not informative, although the authors themselves note that these cells are noncycling for the most part, and thus, one would not expect any effect of UCN-01. The study is important not only for the outcomes it achieved but also for the strategic questions it raises about how we will approach certain aspects of new drug development for cancer in the coming years. As a phase I experience, the data in this study do not allow the clear conclusion that UCN-01 added anything of particular value to the FU regimen. A randomized phase II approach would be necessary to discern a real basis for enthusiasm, and these studies have to be appropriately powered to be meaningful. Statistical techniques to assure early stopping in the event of not achieving evidence of prolongation of stable disease would have to be included to assure appropriate engagement of patient and investigator time. Likewise, it could be imagined that a cross-over to UCN-01 plus FU should be available to patients who have progression of disease on FU alone. If appropriately designed, this in itself would provide valuable information. Although the randomized discontinuation strategy of Rosner et al12 is an interesting approach to obtaining analogous data, it is a complex design that may be difficult to explain adequately to patients because it involves stopping what might actually be a useful therapy in some patients. Nonetheless, it would offer an important alternative strategy toward achieving the same end. No matter how the matter is pursued, further investigations of UCN-01 plus FU or, indeed, of any modulator administered with a marginally active chemotherapy would need to be designed in a way that would necessarily be more complex than the usual type of single-agent drug development program. The originating company of UCN-01 has elected not to pursue its development as a single agent in its current formulation, although it has generously and enthusiastically made available its preclinical development package to the National Cancer Institute (NCI) and, furthermore, continues to support trials sponsored by NCI by supply of clinical bulk material. UCN-01 is a derivative of staurosporine, which was originally proposed as a selective, although not specific, inhibitor of protein kinase C (PKC).13 Subsequent studies revealed that, although UCN-01 is indeed a selective nanomolar inhibitor of PKC isoforms alpha, beta, and gamma,14 its antiproliferative mechanisms were complex and not relatable simply to PKC inhibition.15 In cells with a replete retinoblastoma protein, UCN-01 caused potent downregulation of cyclin-dependent kinase (CDK) activity, in conjunction with arrest in the G1 cell cycle phase,16 leading it to be characterized as a CDK inhibitor. Although this is certainly true in living cells, it reflects the action of the drug on upstream modulators of CDK function because it directly inhibits CDK activity in an enzymatic sense only at higher drug concentrations and, in living cells, actually transiently stimulates CDK activity before ultimately causing CDK inhibition.15 Additional activities include potent nanomolar activity to inhibit the DNA damage checkpoint enforcing kinases Chk1 and possibly Chk2.17,18 In this latter application, UCN-01 sensitizes cells to a range of DNA-damaging agents, including radiation, platinums, and alkylating agents.19 Most recently, Sato et al have20 demonstrated that the drug inhibits phosphatidylinositol-dependent kinase 1 activity, again in the nanomolar range. This observation is important because it would serve as a basis for downregulating signaling through the akt pathway because phosphatidylinositol-dependent kinase 1 is responsible for activating akt (protein kinase B), which in turn contributes to the enhanced survival of neoplastic cells through a plethora of mechanisms.21 Therefore, UCN-01 has the capacity to modulate the activity of several pathways relevant to proliferation, DNA repair, and cell survival that do not overlap with the activities of compounds being pursued in the corporate sector. UCN-01 has not yet had the full range of clinical studies that would properly evaluate its modulator functions in concert with conventional cytotoxic or other signaling agents. The problem with agents like UCN-01 is related to the question of who will take the lead in developing drugs that have a basis for clinical enthusiasm that arises from the groves of academe rather than from the tables of the corporate boardroom. Where the corporate deep pockets to underwrite such complex development schemes are lacking, the basis for even public underwriting of such efforts is shaky because it is unclear who would pursue a registration-directed indication. In practical terms, UCN-01 may be evolving into an orphan drug, not because of lack of potential application to experimental and perhaps clinical questions but because of the lack of a sponsor that will pursue it vigorously. Analogous issues have arisen with fenretinide in neuroblastoma,22 safingol,23 and other agents without commitment from potential corporate partners. The NCI should be congratulated for supporting peer-reviewed efforts to develop these agents. Perhaps it is time for NCI to go the next step and actively pursue registration-oriented strategies for appropriately reviewed agents without corporate sponsorship or interest. If a company owns the relevant molecule but is not developing it, obtaining its assent would be a normal part of this process. Decision making to support such activities should broadly engage the academic drug discovery and development community and might be an additional valuable use of cooperative group expertise and disease-oriented resources. In a best-case scenario, companies currently marketing oncologic agents might actually support these efforts through a publicly administered fund, perhaps in return for extension of exclusivity applied to their own marketed agents. In the event that a particular development campaign is successful, the US government should feel empowered and encouraged to market the agent itself in a way that is realistically in touch with the cost of the agent's manufacture and testing or outsource it to companies that would be able to use NCI-originated data to allow registration strategies to proceed. In the event that a particular development campaign fails, although we will lament the poor outcome as a wish unfulfilled that was thwarted by cancer as a formidable foe, the drug in question will not have been an opportunity missed solely because of the realities of our business environment. Academia will remain the source of numerous hypotheses leading to opportunities for new cancer treatments. The number and potential value of such efforts will only increase in the coming years as first-generation molecularly targeted agents that have not been fully explored go off patent. We should have in place a system to pursue their promise even if the hypotheses emerge from a noncorporate agenda, while we continue to recognize and embrace the important contributions that private companies of all sizes have made in oncology drug discovery and development. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
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4. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 5. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342
6. Kortmansky J, Shah MA, Kaubisch A, et al: Phase I trial of the cyclin-dependent kinase inhibitor/protein kinase C inhibitor UCN-01 in combination with 5FU in patients with advanced solid tumors. J Clin Oncol 23:1875-1884, 2005 7. Hsueh CT, Kelsen D, Schwartz GK: UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent fashion. Clin Cancer Res 4:2201-2206, 1998[Abstract]
8. Hsueh CT, Wu YC, Schwartz GK: UCN-01 suppresses E2F-1 mediated by ubiquitin-proteasome-dependent degradation. Clin Cancer Res 7:669-674, 2001 9. Hillenbrand A, Formentini A, Staib L, et al: A longterm follow-up study of thymidylate synthase as a predictor for survival of patients with liver tumors receiving hepatic arterial infusion therapy. Eur J Surg Oncol 30:407-413, 2004[CrossRef][Medline]
10. Sausville EA, Arbuck SG, Messmann R, et al: Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J Clin Oncol 19:2319-2333, 2001 11. Hakimian RR, Edelman MJ, Bauer K, et al: Phase I and pharmacokinetic study of the cyclin dependent kinase inhibitor UCN-01 and carboplatin in solid tumors. Proc Am Soc Clin Oncol 22:149, 2003 (abstr 598)
12. Rosner GL, Stadler W, Ratain MJ: Randomized discontinuation design: Application to cytostatic anti-neoplastic agents. J Clin Oncol 20:4478-4484, 2002 13. Takahashi I, Saitoh Y, Yoshida M, et al: UCN-01 and UCN-02, new selective inhibitors of protein kinase C: II. Purification, physicochemical properties, structural determination, and biological activities. J Antibiot (Tokyo) 42:571-576, 1989[Medline] 14. Saenaeve CM, Kazanietz M, Blumberg P, et al: Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue. Mol Pharmacol 45:1207-1214, 1994[Abstract] 15. Wang Q, Worland PJ, Clark JL, et al: Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cyclin dependent kinases 1 and 2. Cell Growth Differ 6:927-936, 1995[Abstract]
16. Akiyama T, Yoshida T, Tsujita T, et al: G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of RB and CDK2 proteins as well as induction of CDK1 inhibitor p21/Cip1/WAF1/Sdi 1 in p53 mutated human epidermoid carcinoma A431 cells. Cancer Res 57:1495-1501, 1997
17. Graves PR, Yu L, Schwartz JK, et al: The chk1 protein kinase and the cdc25C regulatory pathway are targets of the anti-cancer agent UCN-01. J Biol Chem 275:5600-5605, 2000
18. Yu Q, LaRose J, Zhang H, et al: UCN-01 inhibits p53 up-regulation and abrogates gamma-radiation-induced G(2)-M checkpoint independently of p53 by targeting both of the checkpoint kinases chk2 and chk1. Cancer Res 62:5743-5748, 2002 19. Monks A, Harris ED, Vaigro-Wolff A, et al: UCN01 enhances the in vitro toxicity of clinical agents in human tumor cell lines. Invest New Drugs 18:95-107, 2000[CrossRef][Medline] 20. Sato S, Fujita N, Tsuruo T: Interference with PDK1-Akt signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 21:1727-1738, 2002[CrossRef][Medline]
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22. Wang H, Mauer BJ, Reynolds CP, et al: N-(4-hydroxyphenyl)retinamide elevates ceramide in neuroblastoma cell lines by coordinate inactivation of serine palmitoyltransferase ceramide synthase. Cancer Res 61:5102-5105, 2001 23. Schwartz GK, Ward D, Saltz L, et al: A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. Clin Cancer Res 3:537-543, 1997[Abstract]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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