New Directions for Biologic Targets in Urothelial Carcinoma
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Published OnlineFirst May 9, 2012; DOI: 10.1158/1535-7163.MCT-11-0756 Molecular Cancer Review Therapeutics New Directions for Biologic Targets in Urothelial Carcinoma Suzanne Richter and Srikala S. Sridhar Abstract Urothelial carcinoma remains an important oncologic problem with significant morbidity and mortality. This article provides an overview of the current status of treatment of urothelial carcinoma, with an update on current trials and recent American Society of Clinical Oncology abstracts. As an alternative to focusing on the metastatic setting, we take a broad look at drug development to date, as it spans from early disease to advanced disease in the context of emerging molecular data. This approach allows us to show that each stage involves key considerations based on emerging evidence regarding molecular biology, stage-specific novel endpoints, and rational patient selection that may help further trial designs in the future. Key issues, such as neoadjuvant versus adjuvant perioperative chemotherapy, approaches to salvage second-line therapy in the metastatic setting, and treatment of elderly and cisplatin-ineligible patients, are discussed. New paradigms in clinical research, including novel endpoints, upfront rational patient selection, biomarkers, and trial design, are also addressed. Mol Cancer Ther; 1–10. Ó2012 AACR. Introduction which incorrectly implies nonaggressive disease). Urothelial carcinoma, which can affect the bladder, NMIUC is a heterogeneous group of cancers with a markedly diverse prognosis, including Ta (papillary), ureters, or renal pelvis, is the sixth most common cancer in situ overall, accounting for 70,000 new cases and 18,000 T1 (invades the submucosa), and Tis [carcinoma deaths in North America in 2010 (1). Urothelial carci- (CIS)] cancers. Whereas low-grade Ta tumors frequently noma has 3 main presentations: nonmuscle-invasive recur and infrequently progress to muscle-invasive dis- disease, muscle-invasive disease, and metastatic dis- ease, high-grade Ta, T1, and Tis tumors often progress and ease. Conventional management has reached a thera- have worse outcomes. NMIUC is managed conservatively peutic plateau at all stages of the disease, but recent by transurethral resection with adjuvant intravesical ther- advances in molecular biology have identified new apy for patients with high-risk features, such as high- therapeutic targets that may translate into better treat- grade, large, or multifocal tumors; CIS; or recurrent ments and improved outcomes. This article provides an tumors (2). Although a number of intravesical agents, overview of the current treatment options and ongoing such as mitomycin C and doxorubicin, have been tried, and reported clinical trials from PubMed, the Clinical immunotherapy with Bacille Calmette-Guerin (BCG) is Trials.gov database, and American Society of Clinical the most commonly used treatment. BCG eradicates resid- Oncology abstracts. Key issues, such as neoadjuvant ual tumor and reduces the risk of recurrence, but up to one versus adjuvant chemotherapy, salvage second-line third of patients will still experience recurrence, requiring options, and treatment of cisplatin-unfit patients, as repeat transurethral resection and sometimes cystectomy, well as aspects of clinical trial design (e.g., patient which is associated with considerable morbidity (3). selection, biomarkers, and novel endpoints), are also Trials of newer chemotherapies, targeted therapies, and discussed. immune-based approaches are under way (Table 1). For BCG-refractory patients, early results from a phase I/II Nonmuscle-Invasive Disease study of intravesical nab-paclitaxel, a novel albumin- bound form of paclitaxel, are encouraging (4). Sunitinib, Approximately 70% of newly diagnosed cases of an oral VEGF tyrosine kinase inhibitor (TKI) that has been urothelial carcinoma are nonmuscle-invasive urothelial approved in metastatic kidney cancer, and the antisense carcinoma (NMIUC; previously called superficial disease, oligonucleotide OGX-427 to HSP27 are 2 targeted thera- pies that are also being studied in NMIUC (5, 6). Immu- nomodulatory approaches, such as using a combination of Authors' Affiliation: Department of Medical Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada interferon and BCG or a mycobacterial cell wall DNA complex (MCC), are also being explored (7, 8). MCCs exert Corresponding Author: Srikala S. Sridhar, Department of Medical Oncol- ogy, Princess Margaret Hospital, 5-222, 610 University Avenue, Toronto, their anticancer activity by inducing anticancer cytokines Ontario, Canada M5G 6M9. Phone: 416-946-4501, ext. 2662; Fax: 416- and having a direct proapoptotic effect on cancer cells (9). 946-6546; E-mail: [email protected] Perhaps the greatest potential for developing new treat- doi: 10.1158/1535-7163.MCT-11-0756 ments lies in the understanding that NMIUC may actually Ó2012 American Association for Cancer Research. be 2 distinct diseases (low-grade and high-grade), each www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst May 9, 2012; DOI: 10.1158/1535-7163.MCT-11-0756 Richter and Sridhar Table 1. Current active phase II and III trials in NMIUC Agent(s) Setting Triala Correlates DTA-H19/PEI Phase IIb, second line NCT00595088 Sunitinib Phase II, second line NCT01118351 CTCs, Tregs, angiogenic markers MCC Phase II/III NCT00406068 BCG Æ gefitinib Phase III NCT00352079 Intravesicular nab-paclitaxel Phase I/II NCT00583349 Abbreviations: CTC, circulating tumor cell; Treg, regulatory T cell. aClinicalTrials.gov registry number. with its own morphology, molecular profile, and biologic 25%–30% with extravesical extension. Attempts to behavior. Low-grade papillary tumors are often multi- improve survival have focused on the use of perioperative focal, rarely progress, and are associated with mutations (neoadjuvant or adjuvant) chemotherapy, but many in the fibroblast growth factor receptor 3 (FGFR3) path- issues remain to be resolved, including the optimum way leading to constitutive activity via downstream Ras timing for chemotherapy, the ideal chemotherapy regi- signaling pathways (10). FGFR3 is an attractive therapeu- men, and how best to personalize perioperative treatment. tic target in these cancers because 60% of mutations occur at a single hotspot that is amenable to screening. Both Adjuvant chemotherapy tyrosine kinase inhibition with the FGFR TKI dovitinib The main advantage of chemotherapy given after sur- and shRNA knockdown of S249C (the most common gery or adjuvant chemotherapy is that there is no delay to FGFR3 mutation) have shown preclinical inhibition of definitive local therapy, and complete pathologic staging cell proliferation in low-grade cancers (11, 12). In contrast, is available before systemic treatment is administered. high-grade tumors (commonly flat tumors, CIS, or occa- The biggest disadvantages are the delay to systemic treat- sionally papillary tumors) have increased invasive poten- ment against micrometastatic disease, inability to assess tial and show inactivation of the tumor suppressor genes chemosensitivity, tolerability in the postoperative period, retinoblastoma (RB) and p53. Mechanisms for p53 inacti- and patient refusal. To date, most large adjuvant chemo- vation include direct mutation or alteration of p53-inter- therapy trials have been small, underpowered, stopped acting proteins, such as MDM2. MDM2 is an E3 ligase early, or had variability in the chemotherapy regimens responsible for ubiquitin-dependent degradation. It is used. Furthermore, the allotted treatments often were not overexpressed in 30% of patients with urothelial carci- received, which made it difficult to determine the benefit noma, and is linked to high-grade tumors. Several agents of adjuvant chemotherapy with any precision. aimed at restoring p53 function either directly or through Two of 6 completed randomized trials have shown a their interaction with modifiers such as MDM2 are in survival benefit. Skinner and colleagues (15) randomized development and may prove to be beneficial for high- 91 patients to cystectomy plus adjuvant cisplatin, cyclo- grade disease (13). phosphamide, and doxorubicin or cystectomy alone, and NMIUC provides an example of how we can achieve showed a prolonged disease-free survival (DFS) at 5 years rational drug development by matching clinical and molec- of 51% for adjuvant chemotherapy versus 34% for no ular characteristics to specific targeted therapies. For low- adjuvant chemotherapy (P ¼ 0.011), but no difference in grade disease due to FGFR3 mutations, the FGFR TKIs may overall survival (OS). A trial by Lehmann and colleagues be particularly effective, even if they lack activity in (16) in which pT3-pT4a and/or Nþ patients were ran- advanced disease. Similarly, as p53-reactivating agents domized postcystectomy to methotrexate, vinblastine, proceed into phase II studies, enriching clinical trials for Adriamycin, and cisplatin (MVAC); methotrexate, vin- high-grade disease and p53-inactivating mutations may blastine, epirubicin, and cisplatin (MVEC); or no chemo- increase our chance of seeing a benefit with these new therapy was stopped after an interim analysis showed a agents. This shift in trial design, where molecular pheno- progression free-survival (PFS) of 43.7% versus 13.0% (P ¼ type is used to select patients, may ultimately lead to 0.002) and OS of 26.9% versus 17.4% (P ¼ 0.069), support- greater success in drug development