Kohli, Manish

Cardiac metastasis in renal cell carcinoma is a very rare entity, with only a few previously reported cases. In this series, we report two cases of ventricular metastases from renal cell carcinoma without vena cava or right atrial involvement. The first case involves an initially isolated inoperable metastasis to the left ventricle, which was treated with systemic targeted therapy with favorable local response. Our second case illustrates a patient with an isolated cardiac metastasis in the interventricular septum with extension into the right ventricle, which has also remained stable in size on systemic targeted therapy. Although anti-angiogenic agents such as tyrosine kinase inhibitors have transformed the treatment of metastatic renal cell carcinoma in recent years, their efficacy and safety in treating patients with metastatic disease in highly vascular organs such as the heart are currently unknown, with no prior reports on this topic. We describe our novel management of these unique cases and discuss the current medical and surgical approaches to treating cardiac metastases from renal cell carcinoma.

Recent therapeutic advances for managing advanced prostate cancer include the successful targeting of the androgen-AR axis with several new drugs in castrate resistant prostate cancer including abiraterone acetate and enzalutamide (MDV3100). This translational progress from “bench to bed-side” has resulted in an enlarging repertoire of novel and traditional drug choices now available for use in advanced prostate cancer therapeutics, which has had a positive clinical impact in prolonging longevity and quality of life of advanced prostate cancer patients. In order to further the clinical utility of these drugs, development of predictive biomarkers guiding individual therapeutic choices remains an ongoing challenge. This paper will summarize the potential in developing predictive biomarkers based on the pathophysiology of the androgen-AR axis in tumor tissue from patients with advanced prostate cancer as well as inherited variation in the patient’s genome. Specific examples of rational clinical trial designs incorporating potential predictive biomarkers from these pathways will illustrate several aspects of pharmacogenetic and pharmacogenomic predictive biomarker development in advanced prostate cancer therapeutics.

Abstract Mortality from prostate cancer in 2011 is estimated at 33,720 deaths in United States which occurs primarily in advanced disease stages. The cornerstone treatment of advanced prostate cancer is androgen deprivation, first established by Huggins and Hodges in 1941. Since then, recognition for the central role of the androgen axis and the androgen receptor (AR) during prostate tumorigenesis and progression, has been accepted. The arrest of the androgen-dependent growth stimulus by surgical or medical castration (with LHRH analogues or antagonists) is the result of reduced circulating androgens including dihydro-testosterone (DHT), which induces apoptotic regression of androgen-dependent cancer cells. This control however is short lived with the emergence of castration-resistant prostate cancer (CRPC). Despite achieving sub-castrate levels of circulating androgens as a result of castration, the androgen-AR axis continues to play an active role in tumor progression. A functional AR, despite the paucity of circulating androgens, is evidenced by the elevation of AR mRNA and re-expression of some androgen-regulated genes during clinical castration, indicative of a persistently activated AR cell signaling pathway. Furthermore, although testosterone and DHT are depleted in serum following traditional androgen deprivation therapy, significant levels of androgens have been measured in locally CRPC tissue1 as well as in metastatic CRPC tissue2. These androgens continue to regulate AR transcriptional activity and stimulate expression of androgen-regulated genes thereby re-invigorating tumor progression. Indeed, a number of molecular and cellular changes have been shown to facilitate activation of the AR under these conditions: amplification of the AR gene allow the receptor to respond to lower levels of androgens; splice variants of the AR exhibit constitutive activity; increased expression of several co-activator proteins enhance activation of the AR; other signaling pathways, including Akt-PI3 Kinase and MAP Kinase, activate the AR; and gain-of-function mutations in the AR allow the receptor to become “promiscuous” and then bind to ligands other than DHT, including anti-androgens3 and weaker sex steroids such as androstenedione. Abiraterone acetate, a selective steroidal irreversible inhibitor of CYP17 (17 hydroxylase/C17,20-lyase) blocks two important enzymatic activities in the synthesis of testosterone4. In a phase III trial in patients progressing on docetaxel chemotherapy, the combination of abiraterone plus prednisone resulted in an improvement in overall survival compared to patients receiving prednisone plus placebo (14.8 months vs 10.9 months, HR=0.646;P<0.001)5. The PSA response to the active drug combination was 38% vs 10% for the placebo group. A second phase III trial testing abiraterone with prednisone vs placebo and prednisone in the castration resistant stage in patients who are chemotherapy naïve has completed accrual (COU-AA-302; NCT00887198). These results re-enforce the rationale behind previous similar clinical attempts in which non-selective and reversible inhibitors of sex steroid biosynthesis such as ketoconazole in combination with hydrocortisone were used6 to target androgen biosynthesis after failure of androgen deprivation therapy. Ketoconazole inhibits the cholesterol side chain cleavage enzyme 11 beta hydroxylase as well as CYP 17, albeit reversibly7. While no overall survival difference for the study group was demonstrated in this study, an increased survival was observed in patients treated with ketoconazole experiencing PSA responses (35% with a 50% decline in PSA). Interestingly, CYP 17 inhibition with abiraterone in CRPC patients may retain activity even in patients previously treated with ketoconazole8. Adverse events with abiraterone use include hypokalemia, hypertension, peripheral edema and headaches all sequelae of secondary mineralocorticoid excess which can be minimized with the use of combination prednisone. Additional drugs in development include Ortrenol (previously named TAK-700; Millenium Pharmaceuticals, Cambridge, MA/Takeda, Osaka, Japan), which inhibits CYP 17, 20 lyase more potently than 17-hydroxylase. Two on-going large phase III studies with ortrenol in combination with prednisone in chemotherapy naïve (ClinicalTrials.gov Identifier: NCT 01193244) and in the post docetaxel chemotherapy (ClinicalTrials.gov Identifier: NCT01193257) CRPC populations will evaluate response of the study combination vs prednisone plus placebo with overall survival as the primary endpoint. Another novel drug is ToK-001 (Tokai Pharmaceuticals, Cambridge, MA) which is a combined inhibitor of CYP 17 and AR currently in early clinical phase II trials. Resistance to abiraterone has been observed in patients initially responding to the drug. Xenograft models suggest that the resistance may occur through upregulation of CYP17A1 and/or induction of AR and AR splice variants that confer ligand independent AR transactivation9. Targeting the AR with next generation AR inhibitors has also emerged as a potential therapeutic maneuver in CRPC. MDV310010 (Medivation, San Francisco, CA), a second generation anti-androgen, is now in phase III clinical trials. This new diarylthiohydantoin compound targets AR by binding over-expressed AR with an affinity that is several fold greater than previously obtained with anti-androgens (bicalutamide and flutamide). Another drug, ARN-509 (Aragon, San Diego, CA) is currently in phase I/II clinical trials (NCT01171898) and further development of this drug is to be determined based on the completion of the on-going dose establishing trial. Both these drugs disrupt the nuclear translocation of AR and impair DNA binding to androgen response elements and recruitment of co-activators and thus have multi-functional anti-tumor capabilities10. Results of a phase III study with the primary endpoint of overall survival evaluating MDV3100 vs placebo in the post chemotherapy, castration resistant stage which has completed accrual is now awaited (NCT00974311). Another phase III study is currently accruing patients after androgen deprivation failure who are chemotherapy naïve evaluating MDV3100 vs placebo also with the primary endpoint of overall survival (NCT01212991). In conclusion, the AR signaling axis remains active during the progression to CRPC and should be considered to be a viable target for therapy. References: 1. Mohler JL. Castration-recurrent prostate cancer is not androgen-independent. Adv Exp Med Biol. 2008;617:223–234. 2. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447–4454. 3. Dehm SM, Tindall DJ. Molecular regulation of androgen action in prostate cancer. J Cell Biochem. 2006;99:333–344. 4. Reid AH, Attard G, Barrie E, de Bono JS. CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Clin Pract Urol. 2008;5:610–620. 5. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005. 6. Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2004;22:1025–1033. 7. Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C, Hartmann RW. Effects of novel 17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol. 2003;84:555–562. 8. Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28:1481–1488. 9. Mostaghel EA, Marck BT, Plymate SR, et al. Resistance to CYP17A1 Inhibition with Abiraterone in Castration-Resistant Prostate Cancer: Induction of Steroidogenesis and Androgen Receptor Splice Variants. Clinical cancer research: an official journal of the American Association for Cancer Research. 2011;17:5913–5925. 10. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–790. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN08-01.

Azadirachta indica(common name: neem) leaves have been found to possess immunomodulatory, anti-inflammatory and anti-carcinogenic properties. The present study evaluates anti-angiogenic potential of ethanol extract of neem leaves (EENL) in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with EENL inhibited VEGF induced angiogenic responsein vitroandin vivo. Thein vitroproliferation, invasion and migration of HUVECs were suppressed with EENL. Nuclear fragmentation and abnormally small mitochondria with dilated cristae were observed in EENL treated HUVECs by transmission electron microscopy. Genome-wide mRNA expression profiling after treatment with EENL revealed differentially regulated genes. Expression changes of the genes were validated by quantitative real-time polymerase chain reaction. Additionally, increase in the expression of HMOX1, ATF3 and EGR1 proteins were determined by immunoblotting. Analysis of the compounds in the EENL by mass spectrometry suggests the presence of nimbolide, 2′,3′-dehydrosalannol, 6-desacetyl nimbinene and nimolinone. We further confirmed antiproliferative activity of nimbolide and 2′,3′-dehydrosalannol in HUVECs. Our results suggest that EENL by regulating the genes involved in cellular development and cell death functions could control cell proliferation, attenuate the stimulatory effects of VEGF and exert antiangiogenic effects. EENL treatment could have a potential therapeutic role during cancer progression.