Trop-2 expression on treatment resistant cancer cells in castrate-resistant prostate cancer (CRPC) as a predictive biomarker for targeted therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5045-5045
Author(s):  
Kimberly Peihsi Ku ◽  
Joshua Michael Lang ◽  
Jamie Sperger ◽  
Scott Dehm ◽  
Manish Kohli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Clinical Trial ◽  
Splice Variant ◽  
Splice Variants ◽  
Predictive Biomarker ◽  
Antibody Drug Conjugate ◽  
Neuroendocrine Markers ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

5045 Background: Trophoblastic cell-surface antigen (Trop-2) is a transmembrane glycoprotein that is highly expressed in many solid tumors. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate of an anti-Trop-2 humanized antibody with SN-38. Early clinical trials have shown high response rates in a broad range of diseases including triple negative breast and urothelial cancers. We evaluated Trop-2 expression in tumor biopsies and circulating tumor cells (CTCs) from men with mCRPC (metastatic castrate-resistant prostate cancer). Methods: Trop-2 expression was evaluated from mCRPC biopsies from patients (Pts) treated with abiraterone acetate (AA) on the PROMOTE clinical trial, CTCs from a separate cohort treated with either enzalutamide or AA. Trop-2 CTCs were compared with EpCAM captured CTCs using a microscale technology termed the VERSA (Vertical Exclusion-based Rare Sample Analysis) platform to compare protein and gene expression signatures of resistance to these agents. Results: RNA sequencing identified Trop-2 gene expression in > 70% of metastatic biopsies. The AR splice variant V7 was found in 48 biopsies that also expressed Trop-2. Trop-2 expression was not altered by treatment with AA at 12 weeks. The number of CTCs captured from 25 pts with Trop-2 or EpCAM were closely correlated (R2= 0.84). Gene expression analysis showed similar patterns of expression for the TROP-2 and EPCAM captured cells. AR splice variant expression (AR-V7, AR-V9) in Trop-2 and EpCAM CTCs was detected in 33% of patients. Expression of neuroendocrine markers was identified in 40% of Trop-2 CTCs. Conclusions: Trop-2 is frequently expressed in mCRPC and co-expressed in tumors that express AR splice variants. Trop-2 CTCs are detected in CRPC pts previously treated with AA or Enzalutamide that also express multiple AR splice variants and neuroendocrine markers. The results support Trop-2 expression as predictive biomarker of sensitivity to targeted therapies tumors resistant to AA or Enzalutamide. Men with mCRPC are being enrolled on a Phase I trial with IMMU-132, and multi-site Phase II clinical trial in men who have progressed on AA or Enzalutamide is being finalized.

TROP-2 co-expression with androgen receptor splice variants as a new therapeutic target in prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5060-5060
Author(s):  
Charlotte Stahlfeld ◽  
Jamie Sperger ◽  
Susan F. Slovin ◽  
Scott T. Tagawa ◽  
Christos Kyriakopoulos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Clinical Trial ◽  
Androgen Receptor ◽  
Protein Expression ◽  
Cancer Cell ◽  
Therapeutic Target ◽  
Splice Variant ◽  
Splice Variants ◽  
Gene Signatures

5060 Background: Tumor-associated calcium signal transducer 2 (TROP-2, TACSTD2) is a transmembrane glycoprotein that is highly expressed in many epithelial cancers. Overexpression of TROP-2 is postulated to mediate cancer cell growth, invasion, and is associated with more aggressive disease. TROP-2 has emerged as a therapeutic target for antibody-drug conjugates in clinical trials including sacituzumab govitecan and DS-1062. Here, we evaluated the expression of TROP-2 in tumor biopsies and circulating tumor cells (CTCs) in men with metastatic castration resistant prostate cancer (mCRPC) to evaluate TROP-2 as a clinically relevant target. Methods: RNA-seq data from the SU2C-PCF database and PROMOTE clinical trial (NCT#01953640) was assessed for TACSTD2 and androgen receptor (AR) splice variant ( AR_V7/AR_V9) expression. Prostate cancer ChIP-seq data was analyzed to identify binding of the AR to the TROP-2 promoter. EpCAM and TROP-2 captured CTCs were isolated from patients with mCRPC using the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform and assessed for splice variant, neuroendocrine (NE), and AR-regulated gene signatures, in addition to CTC enumeration and TROP-2 protein expression. Results: TROP-2 expression was detectable in 90% of patients, in both bone and visceral metastatic biopsies (SUC2-PCF). Although TROP-2 low biopsies were infrequent (10%), 58% of these samples showed high levels of NE markers, as compared with 5% in all other patients. In the PROMOTE study, elevated TROP-2 gene expression was significantly higher in biopsies with high AR_V7 expression than in those with low (p = 0.04) or negative (p <.01) AR_V7 expression. ChIP-seq data demonstrated binding of AR at the TROP-2 promoter as well as at a potential enhancer site upstream, suggesting that TROP-2 expression can be regulated by AR activity. Splice variants and NE gene signatures were expressed in CTCs captured with both EpCAM and TROP-2, although markedly different gene expression profiles between EpCAM and TROP-2 CTCs were observed in a subset of patients with neuroendocrine prostate cancer. Detection of AR_V7 from TROP-2 CTCs corresponded to shorter overall survival in 20 patients with mCRPC. TROP-2 protein expression was identified on EpCAM captured CTCs, although patients exhibited a wide degree of both intra- and inter-patient heterogeneity. Conclusions: Our findings demonstrate that TROP-2 is highly expressed in mCRPC, and is reduced in a subset of patient tumors expressing neuroendocrine markers. In the PROMOTE clinical trial with abiraterone acetate, TROP-2 AR variant expression correlated with increased TROP-2 expression. Binding of the AR to the TROP-2 promoter and potential enhancer was observed in prostate cancer cell lines and biopsies. These results indicate TROP-2 is a high value a biomarker and therapeutic target mCRPC.

Overall survival after 177Lu-PSMA-617 molecular radiotherapy in patients with metastatic castrate-resistant prostate cancer: Post-hoc analysis of a prospective phase II trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5549-5549 ◽  
Author(s):  
Jeremie Calais ◽  
Jeannine Gartmann ◽  
Wesley R Armstrong ◽  
Pan Thin ◽  
Kathleen Nguyen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Post Hoc Analysis ◽  
Molecular Radiotherapy ◽  
Prospective Phase ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Post Hoc

5549 Background: This was an open-label randomized prospective bi-centric single-arm phase II clinical trial of 177Lu-PSMA-617 molecular radiotherapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC) conducted at University of California Los Angeles (USA) and Excel Diagnostics & Nuclear Oncology Center (Houston, TX, USA) (NCT03042312). The study was investigator-initiated under an investigational new drug approval protocol (IND#133661) with authorization of charging for investigational drug (cost-recovery, Title 21 CFR 312.8). We report here the post-hoc analysis of overall survival (OS) in a single-study site cohort (UCLA). Methods: Patients with progressive mCRPC (biochemical, radiographic, or clinical) after ≥1 novel androgen axis drug (NAAD), either chemotherapy (CTX) naïve or post-CTX, with sufficient bone marrow reserve, normal kidney function, and sufficient PSMA-target expression by PET were eligible. Patients received up to 4 cycles of 177Lu-PSMA-617 every 8±1 weeks and were randomized into 2 treatment activities groups (6.0 or 7.4 GBq). Efficacy was defined as serum PSA decline of ≥50% from baseline and served as primary endpoint (hypothesis: ≥40% of responders after 2 cycles). Results: 43 patients were randomized to the 6.0 GBq (n= 14) and 7.4 GBq (n=29) treatment arms. 11/43 (26%) were CTX naïve while 10/43 (23%), 12/43 (28%), 5/43 (12%) and 5/43 (12%) had received 1, 2, 3 or 4 CTX regimens. Median baseline PSA was 29.2 ng/ml (mean 228.8, range 0.5-2082.6). 21/43 (49%) completed 4 cycles of 177Lu-PSMA-617 whereas 4/43 (9%), 13/43 (30%) and 5/43 (12%) underwent 1, 2 and 3 cycles. PSA decline of ≥50% was observed in 11/43 of patients (26%) after 2 cycles and in 16/43 (37%) at any time (best PSA response). 9/43 (21%) had a PSA decline of ≥90% and 23/43 (53%) had any PSA decline (>0%). After a median follow-up of 19.5 months the median OS was 14.8, 15.7 and 13.5 months in the whole cohort, the 6.0 GBq and 7.4 GBq treatment arms, respectively (p=0.68). Patients showing a PSA decline of ≥50% after 2 cycles and at any time had a longer OS: median 20.1 months vs. 13.6 (p=0.091) and 20.1 vs. 11.6 (p=0.002), respectively. Conclusions: In this post-hoc analysis of a single-site cohort of 43 patients included in a prospective phase II trial the median OS after 177Lu-PSMA-617 molecular radiotherapy in patients with progressive mCRPC was 14.8 months. There was no difference of efficacy between the 6.0 GBq and 7.4 GBq treatment arms. Clinical trial information: NCT03042312 .

scholarly journals Glucocorticoid Receptor is distinct from Androgen Receptor function in Castrate-Resistant Prostate Cancer

2020 ◽  
Author(s):  
Dalal El-Barbarawi ◽  
Tiha M Long
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Androgen Receptor ◽  
Glucocorticoid Receptor ◽  
Gene Expression Analysis ◽  
Target Gene ◽  
Invasive Disease ◽  
Published Data ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Commonly used therapies for prostate cancer (PC) that block androgen receptor (AR) signaling inhibit regrowth, but aggressive castrate-resistant (CR)PC abrogates anti-androgen therapy. Recently published data shows that glucocorticoid receptor (GR) can drive the growth of CRPC when AR is blocked, by mimicking AR activity. Due to the evolution of CRPC into a more invasive disease, we hypothesized that GR-driven CRPC has different activities than AR that promote progression to metastatic disease. To test this hypothesis, we performed gene expression analysis on available datasets to determine which pathways correlate with GR target gene expression. Furthermore, we investigated gene expression in CWR-22Rv1 CRPC cells via qRT-PCR. Our results show that GR-activation in AR-blocked cells induces different genes than AR, suggesting that GR-driven CRPC is unique from AR-driven disease. The scientific contribution of our research may reveal new mechanisms by which GR drives PC progression and unveil novel therapeutic targets.

Prediction of metastatic castrate-resistant prostate cancer response to abiraterone or enzalutamide by a baseline blood-based CTC gene expression signature.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16529-e16529
Author(s):  
Michael Joseph Lariviere ◽  
Naomi B. Haas ◽  
Yauheniya Cherkas ◽  
Karl Nielsen ◽  
Brad Foulk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Prospective Study ◽  
Molecular Mechanisms ◽  
Gene Expression Signature ◽  
Blood Samples ◽  
Expression Signature ◽  
Number Of Patients ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

e16529 Background: Prostate cancer is the most common cancer in men in the U.S., with 30% 5-year overall survival (OS) for patients (pts) with metastases. To take a precision medicine approach to the management of metastatic castrate-resistant prostate cancer (mCRPC), we developed a blood circulating tumor cell (CTC)-based test to identify mCRPC pts most likely to benefit from abiraterone (abi) or enzalutamide (enza). Methods: In this multi-institution prospective study, men with mCRPC were enrolled prior to starting abi (1,000 mg/d plus prednisone 10 mg/d) or enza (160 mg/d). At baseline (BL), 12 w, and progression, blood samples were collected for CellSearch-based CTC enumeration and qPCR-based gene expression analysis. Results: 69 pts (median age 68 y [50-82]) received abi (n = 25) or enza (n = 44) and had evaluable blood samples. Consistent with prior publications, among 43 pts with BL CTC > 0, clearance of detectable CTCs (BL CTCs > 0 and 12 w CTCs = 0), was achieved in 24 patients (55.8%), and was associated with greater median OS (31 mo vs. 18 mo, log-rank p = 0.03). The 43 pts with BL CTC > 0 were then randomly divided into training (n = 31) and validation (n = 12) sets. Baseline gene expression data for the training set was used to develop a model to predict CTC clearance, starting with a panel of 141 expressed genes/isoforms including those associated with prostate cancer. Of the models tested, random forest yielded the best performance, with respective training and validation set sensitivity of 0.7 and 1, specificity 0.75 and 0.71, AUC 0.88 and 0.91. Top genes identified include those previously associated with disease – HOXB13, ESRP2, KLK3, GRHL2, and KRT19, among others. Conclusions: A gene expression signature from a baseline blood sample with CellSearch-enriched CTCs can predict clearance of detectable CTCs in response to abi/enza with high AUC and may give insight into molecular mechanisms of response. A prospective study with a larger number of patients will be required to further validate our findings. Ultimately, this blood test has the potential to select the patients most likely to benefit from second-generation antiandrogen vs. non-hormonal systemic treatment.

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