Novel molecular targets for urothelial carcinoma

Faltas, Bishoy; Karir, Beerinder; Tagawa, Scott T.; Rosenberg, Jonathan E.

doi:10.1517/14728222.2014.987662

Cited by 7 publications

(12 citation statements)

References 79 publications

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“…Advanced chemotherapy-resistant UC remains a formidable clinical challenge with limited therapeutic options 38 . Whole-exome analysis of matched samples from the same patient from different anatomical sites and at sequential time points offers a unique opportunity to reconstruct the evolutionary dynamics and understand the mutagenic pressures shaping the evolution of primary untreated UC to advanced chemotherapy-treated UC.…”

Section: Discussionmentioning

confidence: 99%

Clonal evolution of chemotherapy-resistant urothelial carcinoma

et al. 2016

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Chemotherapy-resistant urothelial carcinoma (UC) has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs UC’s evolution and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 UCs including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated UC is characterized by intra-patient mutational heterogeneity and the majority of mutations are not shared, (ii) both branching evolution and metastatic spread are very early events in the natural history of UC; (iii) chemotherapy-treated UC is enriched with clonal mutations involving L1-cell adhesion molecule (L1CAM) and integrin signaling pathways; (iv) APOBEC induced-mutagenesis is clonally-enriched in chemotherapy-treated UC and continues to shape UC’s evolution throughout its lifetime.

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Section: Discussionmentioning

confidence: 99%

Clonal evolution of chemotherapy-resistant urothelial carcinoma

et al. 2016

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“…The purpose of the current study was to expand and validate the identification of CRGAs in a large series of 295 patients with UCB and demonstrate the impact of targeted therapies in selected patients in whom genomically driven treatment was undertaken. In addition to the original report on 35 cases of UCB, multiple recent studies have been conducted in patients with UCB using a variety of gene sequencing platforms to search for therapy targets . These genome‐wide scanning and CGP techniques identified a series of recurrent potentially targetable genomic alterations in UCB.…”

Section: Discussionmentioning

confidence: 99%

“…From a database of 20,573 consecutive clinical samples of primarily recurrent and refractory solid tumors and hematologic malignancies, 295 cases of UBC were identified. CGP was performed on all formalin‐fixed, paraffin‐embedded tissues using a hybrid capture‐based next‐generation sequencing platform (FoundationOne) at a Clinical Laboratory Improvement Amendments (CLIA)‐certified, New York State‐ and College of American Pathologists‐accredited laboratory (Foundation Medicine, Cambridge, Mass) on the Illumina HiSeq 2500 instrument (Illumina Inc, San Diego Calif) . Formalin‐fixed, paraffin‐embedded slides used for the analyses contained ≥20% tumor tissue.…”

Section: Methodsmentioning

confidence: 99%

“…CGP was performed on all formalin-fixed, paraffinembedded tissues using a hybrid capture-based nextgeneration sequencing platform (FoundationOne) at a Clinical Laboratory Improvement Amendments (CLIA)certified, New York State-and College of American Pathologists-accredited laboratory (Foundation Medicine, Cambridge, Mass) on the Illumina HiSeq 2500 instrument (Illumina Inc, San Diego Calif). 19 Formalin-fixed, paraffin-embedded slides used for the analyses contained 20% tumor tissue. Extracted DNA (at least 50 ng) was adaptorligated and capture was performed for all coding exons from 236 cancer-related and 47 introns of 19 genes frequently rearranged in cancer.…”

Section: Methodsmentioning

confidence: 99%

“…[14][15][16][17][18] However, to the best of our knowledge, studies designed to discover potential therapy targets by performing genomic analysis of clinically aggressive UBC began only recently. [19][20][21] In the current comprehensive genomic profiling (CGP) study of patients with recurrent and refractory UCB, an original database has been expanded from 35 to 295 patients to further refine the landscape of clinically relevant genomic alterations (CRGAs) and to report the results of using targeted therapies for a subset of patients in whom we became aware of therapy selection based on their genomic profiles.…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations

Ross

Wang

Khaira³

et al. 2015

Cancer

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BACKGROUND In the current study, the authors present a comprehensive genomic profile (CGP)‐based study of advanced urothelial carcinoma (UC) designed to detect clinically relevant genomic alterations (CRGAs). METHODS DNA was extracted from 40 µm of formalin‐fixed, paraffin‐embedded sections from 295 consecutive cases of recurrent/metastatic UC. CGP was performed on hybridization‐captured, adaptor ligation‐based libraries to a mean coverage depth of 688X for all coding exons of 236 cancer‐related genes plus 47 introns from 19 genes frequently rearranged in cancer, using process‐matched normal control samples as a reference. CRGAs were defined as GAs linked to drugs on the market or currently under evaluation in mechanism‐driven clinical trials. RESULTS All 295 patients assessed were classified with high‐grade (International Society of Urological Pathology classification) and advanced stage (stage III/IV American Joint Committee on Cancer) disease, and 294 of 295 patients (99.7%) had at least 1 GA on CGP with a mean of 6.4 GAs per UC (61% substitutions/insertions/deletions, 37% copy number alterations, and 2% fusions). Furthermore, 275 patients (93%) had at least 1 CRGA involving 75 individual genes with a mean of 2.6 CRGAs per UC. The most common CRGAs involved cyclin‐dependent kinase inhibitor 2A (CDKN2A) (34%), fibroblast growth factor receptor 3 (FGFR3) (21%), phosphatidylinositol 3‐kinase catalytic subunit alpha (PIK3CA) (20%), and ERBB2 (17%). FGFR3 GAs were diverse types and included 10% fusions. ERBB2 GAs were equally divided between amplifications and substitutions. ERBB2 substitutions were predominantly within the extracellular domain and were highly enriched in patients with micropapillary UC (38% of 32 cases vs 5% of 263 nonmicropapillary UC cases; P<.0001). CONCLUSIONS Using a CGP assay capable of detecting all classes of GA simultaneously, an extraordinarily high frequency of CRGA was identified in a large series of patients with advanced UC. Cancer 2016;122:702–711. © 2015 American Cancer Society.

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Sacituzumab Govitecan, a Novel Antibody–Drug Conjugate, in Patients With Metastatic Platinum-Resistant Urothelial Carcinoma

Faltas

Goldenberg

Ocean

et al. 2016

Clinical Genitourinary Cancer

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Patients with metastatic, platinum-resistant urothelial carcinoma (PRUC) have no Food and Drug Administration-approved therapies. The response rates to second-line chemotherapy have generally been < 20%, with a median overall survival of < 1 year. We report our experience with 6 heavily pretreated patients with advanced PRUC (ClinicalTrials.gov identifier NCT01631552) with the novel antibody-drug conjugate, sacituzumab govitecan (IMMU-132). This antibody-drug conjugate comprises the active metabolite of irinotecan, SN-38, conjugated to an anti-Trop-2 antibody. Trop-2 is widely expressed in ≤ 83% of urothelial carcinomas. Of the 6 patients, 3 had a clinically significant response (progression-free survival, 6.7 to 8.2 months; overall survival, 7.5+ to 11.4+ months). Sacituzumab govitecan was well tolerated. Because of these results, a phase II trial has been initiated. The present report highlights the promise of antibody-drug conjugates, such as sacituzumab govitecan, as a novel therapeutic strategy for the treatment of PRUC.

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Novel molecular targets for urothelial carcinoma

Cited by 7 publications

References 79 publications

Clonal evolution of chemotherapy-resistant urothelial carcinoma

Clonal evolution of chemotherapy-resistant urothelial carcinoma

Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations

Sacituzumab Govitecan, a Novel Antibody–Drug Conjugate, in Patients With Metastatic Platinum-Resistant Urothelial Carcinoma

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