OUTSTANDING POSTER #1
OP1-04: Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Chemotherapy in Muscle Invasive Urothelial CarcinomaAlexander Baras*, Nilay Gandhi, Enrico Munari, Sheila Faraj, Mohammad Hoque, Mark Schoenberg, Trinity Bivalacqua, George Netto, Baltimore, MD
Summary: Neoadjuvant chemotherapy improves survival for patients undergoing radical cystectomy for muscle-invasive urothelial cancers of the bladder. The greatest survival benefit is seen in those patients in whom all cancer is eradicated from the bladder (pT0). However, the prognosis for patients who fail to respond to chemotherapy or progress while on chemotherapy is poor. Predicting who will and will not respond to chemotherapy has huge importance in this area. Researchers from Hopkins identified two genetic markers that could be identified from tissue obtained prior to chemotherapy, to assess the potential response to the medication. Further studies are needed, however these data may help identify patients best served by chemotherapy and those who should forego chemotherapy for a rapid cystectomy.
Introduction and Objectives Neoadjuvant chemotherapy (NAC) results in 5-10% increase in 5-year survival rate in muscle invasive bladder cancer (MIBC) patients. More importantly, those who achieve a complete response (ypT0) have a 5 year survival rate of 80% as opposed to 40% for those who do not. However, NAC is not widely utilized due to concerns related to delay of cystectomy, potential side-effects, and inability to predict effectiveness. Recently suggested molecular signatures of chemoresponsiveness, which could prove useful in this setting, are yet to be translated into clinical practice.
Methods mRNA expression data from a prior report on a NAC-treated MIBC cohort (Kato et. al) were analyzed in combination with the antibody database of the Human Protein Atlas (HPA). We identified classifier candidate biomarkers that can be detected by immunohistochemistry (IHC) in TURB biopsy material prior to NAC. The candidate biomarkers were subsequently validated in an independent cohort of 52 MIBC specimens. Response to NAC was defined as the lack of residual MIBC at cystectomy.
Results By filtering based on large amplitude mRNA changes and the area under the receiver operator curve (AUROC), we identified 21 genes whose mRNA expression profiles differentiate response to NAC (n=33), Figure 1A. Using the HPA, we found that commercially available antibiodies to the protein products of 8 of these genes exhibited differential staining across a set of urothelial carcinomas cataloged in the HPA. In addition, 12 normal tissues were identified from the HPA that can serve as positive and negative controls for the 8 proteins. Our initial studies with 2 of these markers in a multivariate logistic regression model have yielded strong performance (80% accuracy) in identifying patients in our independent validation cohort that are not likely to benefit from NAC due to chemoresistance (Fischer’s exact test p-value 0.02), Figure 1B & 1C.
Conclusions We illustrate the feasibility of translating gene expression signature data on NAC response into an IHC classifier applicable to TURB specimens. The performance achieved by the initial two markers in our study is being further characterized and the other putative protein markers are being assessed in our TMA cohort.
OUTSTANDING POSTER #2
OP1-10: Rho-kinase inhibition prevents nNOS uncoupling in the MPG, erectile dysfunction and increases neuronal outgrowth following cavernous nerve injuryJohanna Hannan*, Xiaopu Liu, Ahmet Hoke, Arthur Burnett, Trinity Bivalacqua, Baltimore, MD
Funding: NIH K08DK090370 and Urology Care Foundation.
Summary: Post-radical prostatectomy erectile dysfunction is a major issue faced by many patients and urologists today. In order to potentially improve ED, inhibition of molecules that potentiate nerve injury, RhoA and RhoKinase (ROCK), an experimental medication was given to rats with a nerve injury. This experiemental medication, U-27632, a ROCK inhibitor, improved post-nerve injury erectile function by preventing nitric oxide degeneration and promoting nerve regrowth and regeneration. This may be a medication suitable to prevent post-prostaetectomy ED in the future.
Introduction and Objectives RhoA and Rho-kinase (ROCK) are implicated in the inhibition axonal growth/neurite sprouting, and neurodegeneration via regulation of inflammation and apoptosis following peripheral nerve injury. We hypothesize that degeneration of the cavernous nerve (CN) after injury is due to increased RhoA/ROCK signaling in the major pelvic ganglion (MPG) leading to neuronal nitric oxide synthase (nNOS) uncoupling and nerve degeneration. This study aimed to characterize the role of ROCK inhibition in preserving erectile responses, penile contractions, nNOS uncoupling and neurite outgrowth following bilateral cavernous nerve injury (BCNI).
Methods Male Sprague-Dawleys rats (12 wks) were separated into sham, BCNI and BCNI treated with Y-27632 (ROCK inhibitor, 5 mg/kg twice daily; n=8/group). 14 days after BCNI, groups underwent CN stimulation to determine erectile function. Penes were dissected and contractile responses to phenylephrine (PE) and electrical field stimulation (EFS) were assessed. MPGs were excised and protein (Western blots) and gene expression (q-PCR) of nNOS and growth associated protein 43 (GAP43) were assessed. Additional MPGs (n=3/group) were cultured in reduced growth factor matrigel for 48h and neurite growth was measured.
Results While erectile function was severely decreased in BCNI rats, daily administration of Y-27632 improved erections 2-fold (p<0.05). nNOS MPG gene expression was decreased by 50% after BCNI and recovered to sham levels with Y-27632 (p<0.05). nNOS uncoupling was increased in BCNI MPGs and completely prevented in y-27632 treated rats (p<0.05). Cavernous contractile responses to PE were unchanged. EFS-mediated penile contractions were significantly lower following BCNI and treatment with Y-27632 increased EFS-mediated contractions 2-fold compared to sham and BCNI penes (p<0.05). MPG neurite outgrowth was unchanged in sham and BCNI; however, BCNI+Y MPGs had significantly increased growth (S:328±9μm; BCNI:349±14μm; BCNI+Y:405±11μm, p<0.05). GAP43, a growth protein highly expressed during axonal regeneration, was increased 25% following BCNI and 30% with Y-27632 treatment indicating treatment increased axonal growth.
Conclusions Inhibition of ROCK preserved erections, prevented nNOS uncoupling, mediated increased neurite growth and increased nerve-mediated penile contractions in BCNI rats. Preventing the activation of RhoA/ROCK signaling in the MPG and CN after injury may inhibit neurodegeneration and post-radical prostatectomy erectile dysfunction.
For more Brady Urological Presentations, visit the AUA2014 Website or stay tuned.
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