Akash Patnaik

A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer

Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss–driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.

New strategies in Prostate Cancer: targeting lipogenic pathways and the energy sensor AMPK

Although the role of metabolic syndrome (MS) and a high fat diet in prostate cancer (PCa) risk is still a matter of intense debate, it is becoming increasingly clear that obesity can cause perturbations in metabolic pathways that contribute to the pathogenesis and progression of PCa. Moreover, prostate epithelial cells per se undergo a series of metabolic changes, including an increase in de novo lipogenesis, during the process of tumor formation. These metabolic alterations, at both the cellular and organismal levels, are intertwined with genetic aberrations necessary for neoplastic transformation. Thus, altered metabolism is currently subject to intense research efforts and might provide preventative and therapeutic opportunities, as well as a platform for biomarker development. In this article, we review evidence that the metabolic sensor 5′-AMP-activated protein kinase (AMPK), which physiologically integrates nutritional and hormonal signals and regulates cell survival and growth-related metabolic pathways to preserve intracellular ATP levels, represents a link between energy homeostasis and cancer. Thus, when AMPK is not activated, as in the setting of MS and obesity, systemic metabolic alterations permissive to the development of PCa are allowed to proceed unchecked. Hence, the use of AMPK activators and inhibitors of key lipogenic enzymes may represent a promising therapeutic strategy for PCa. Clin Cancer Res; 16(13); 3322–8. ©2010 AACR.

Vulnerabilities of PTEN–TP53-Deficient Prostate Cancers to Compound PARP–PI3K Inhibition

UNLABELLED Prostate cancer is the most prevalent cancer in males, and treatment options are limited for advanced forms of the disease. Loss of the PTEN and TP53 tumor suppressor genes is commonly observed in prostate cancer, whereas their compound loss is often observed in advanced prostate cancer. Here, we show that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the prosurvival PI3K-AKT signaling pathway limits the efficacy of a PARP single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human prostate cancer cell lines and in a Pten/Trp53-deficient mouse model of advanced prostate cancer. Our findings, therefore, identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient prostate cancer. SIGNIFICANCE The paucity of therapeutic options in advanced prostate cancer displays an urgent need for the preclinical assessment of novel therapeutic strategies. We identified differential therapeutic vulnerabilities that emerge upon the loss of both PTEN and p53, and observed that combined inhibition of PARP and PI3K provides increased efficacy in hormone-insensitive advanced prostate cancer.

ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer

Purpose: ErbB2 signaling appears to be increased and may enhance androgen receptor (AR) activity in a subset of patients with castration-resistant prostate cancer (CRPC), but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer and to determine whether it may contribute to AR signaling in these tumors. Experimental Design: AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model. Results: We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Furthermore, concomitantly treating CRPC cells with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression. Conclusions: ErbB2 signaling is elevated in a subset of patients with abiraterone-resistant prostate cancer and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity. Clin Cancer Res; 22(14); 3672–82. ©2016 AACR.

Cabozantinib eradicates advanced murine prostate cancer by activating antitumor innate immunity

Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here, we show that cabozantinib rapidly eradicates invasive, poorly differentiated PTEN/p53-deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anticancer innate immune response, resulting in tumor clearance.Significance: This study is the first to demonstrate that a tyrosine kinase inhibitor can activate neutrophil-mediated antitumor innate immunity, resulting in invasive cancer clearance. Cancer Discov; 7(7); 750-65. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.

PI3K Enters Beta-Testing

Phosphoinositide-3-OH kinases (PI3K) are critical regulators of cell metabolism, growth, and survival. In a recent publication in Nature, Jia et al. (2008) identify specific functions of the p110beta isoform of PI3K in glucose metabolism, cellular proliferation, and tumorigenesis.

Evolving Intersection Between Inherited Cancer Genetics and Therapeutic Clinical Trials in Prostate Cancer: A White Paper From the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium

Purpose Advances in germline genetics, and related therapeutic opportunities, present new opportunities and challenges in prostate cancer. The Prostate Cancer Clinical Trials Consortium Germline Genetics Working Group was established to address genetic testing for men with prostate cancer, especially those with advanced disease undergoing testing for treatment-related objectives and clinical trials. Methods The Prostate Cancer Clinical Trials Consortium Germline Genetics Working Group met monthly to discuss the current state of genetic testing of men with prostate cancer for therapeutic or clinical trial purposes. We assessed current institutional practices, developed a framework to address unique challenges in this population, and identified areas of future research. Results Genetic testing practices in men with prostate cancer vary across institutions; however, there were several areas of agreement. The group recognized the clinical benefits of expanding germline genetic testing, beyond cancer risk assessment, for the goal of treatment selection or clinical trial eligibility determination. Genetic testing for treatment selection should ensure patients receive appropriate pretest education and consent and occur under auspices of a research study whenever feasible. Providers offering genetic testing should be able to interpret results and recommend post-test genetic counseling for patients. When performing tumor (somatic) genomic profiling, providers should discuss the potential for uncovering germline mutations and recommend appropriate genetic counseling. In addition, family members may benefit from cascade testing and early cancer screening and prevention strategies. Conclusion As germline genetic testing is incorporated into practice, further development is needed in establishing prompt testing for time-sensitive treatment decisions, integrating cascade testing for family, ensuring equitable access to testing, and elucidating the role of less-characterized germline DNA damage repair genes, individual gene-level biologic consequences, and treatment response prediction in advanced disease.

Abstract 4979: Cabozantinib eradicates advanced murine prostate cancer by activating neutrophil-mediated anti-tumor innate immunity

Several kinase inhibitors targeting aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor, plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anti-tumor innate immune response, resulting in rapid tumor clearance. Citation Format: Akash Patnaik, Kenneth D. Swanson, Eva Csizmadia, Marina P. Gehring, Katja Helenius, Athalia R. Pyzer, Lily C. Wang, Jesse Novak, Olivier Elemento, Thomas B. Thornley, John M. Asara, John G. Clohessy, Kathy Kelly, Pier Paolo Pandolfi, Jacalyn M. Rosenblatt, David E. Avigan, Huihui Ye, Sabina Signoretti, Steven P. Balk, Lewis C. Cantley. Cabozantinib eradicates advanced murine prostate cancer by activating neutrophil-mediated anti-tumor innate immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4979.

Abstract C112: Cabozantinib eradicates advanced murine prostate cancer by activating anti-tumor innate immunity

Several kinase inhibitors targeting aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in early phase clinical trials, particularly in cancer patients with bone metastases. Here we show that cabozantinib rapidly eradicates invasive, poorly-differentiated PTEN/p53 deficient murine prostate cancer. This was associated with increased neutrophil chemotactic factor expression, including CXCL12 and HMGB1 production by tumor cells, and robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor, plerixafor. Collectively, these results demonstrate that cabozantinib triggers neutrophil-mediated anti-tumor innate immune response that results in tumor clearance. (Manuscript submitted to Science) Citation Format: Akash Patnaik, Kenneth Swanson, Sabina Signoretti, Huihui Ye, Eva Csizmadia, Jesse Novak, Marina Gehring, Katja Helenius, Athalia Pyzer, Laleh Montaser, Lily Wang, Olivier Elemento, Elena Levantini, John Clohessy, John Asara, Kathleen Kelly, Pier Paolo Pandolfi, Jacalyn Rosenblatt, David Avigan, Steven Balk, Lewis Cantley. Cabozantinib eradicates advanced murine prostate cancer by activating anti-tumor innate immunity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C112.

Abstract 5497: Cabozantinib eradicatesde novocastrate-resistant PTEN/p53 deficient murine prostate cancer via activation of neutrophil-mediated anti-tumor innate immunity

The majority of kinase inhibitors in cancer clinical trials have been evaluated in the context of cell autonomous induction of apoptosis. However, apoptosis can result in protumorigenic immunosuppression, which limits the durability of an anti-tumor response. Recent clinical trial data shows striking clinical and radiographic responses with kinase inhibitor cabozantinib (XL-184) in metastatic solid tumors, particularly in the context of bone metastases. However, the mechanism responsible for this robust antitumor response remain unknown. Here we show that cabozantinib eradicates poorly differentiated invasive cancer that develop in the context of prostate-specific PTEN and p53 loss, respectively, within 48 hours of cabozantinib treatment. This rapid tumor clearance was temporally associated with infiltration of mature polymorphonuclear leukocytes into the tumor bed. These anti-tumor effects of cabozantinib appear to be MET-independent, since the MET inhibitor PF-04217903 did not phenocopy the effects of cabozantinib in the prostate-specific PTEN/p53 deficient mouse model in vivo. Unexpectedly, in vitro treatment of PTEN/p53 deficient cell lines derived from murine tumors showed insignificant apoptosis, but robust extracellular release of HMGB1, a neutrophil chemoattractant, and marker of immunogenic cell death. To elucidate the relevance of an immunogenic anti-tumor mechanism in vivo, we performed RNA-seq profiling and quantitative RT-PCR analysis, which showed an acute increase in anti-tumor inflammatory cytokine gene expression signature and neutrophil activation/chemotaxis markers following acute cabozantinib treatment. Critically, blockade of neutrophil chemotaxis/trafficking with dexamethasone or depletion with anti-Ly6G antibody, reversed the effects of cabozantinib towards eradication of advanced PTEN/p53 deficient tumors. Finally, cytokine array profiling of supernatant from bone marrow metastases from castrate-resistant prostate cancer patients showed increased neutrophil markers and decreased IL-6 levels within the bone microenvironment following 6 weeks of cabozantinib treatment., thus polarizing the neutrophils into” N1” effector cells. Collectively, these results shed light on a novel anti-tumor immunogenic mechanism for cabozantinib within the tumor microenvironment of PTEN/p53 deficient tumors, which unleashes a profound innate anti-tumor immune response. These findings suggest the possibility of combination therapies of cabozantinib with T-cell checkpoint blockade or vaccine-based approaches, to augment immunologic responses in advanced cancers. Citation Format: Akash Patnaik, Kenneth Swanson, Katja Helenius, Thornley Thomas, Athalia Pyzer, Vilmosne Csizmadia, Sabina Signoretti, Todd Morgan, Yugang Wang, Olivier Elemento, Lily Wang, Elena Levantini, John Clohessy, John Asara, David Smith, Jacalyn Rosenblatt, David Avigan, Steven Balk, Lewis Cantley. Cabozantinib eradicates de novo castrate-resistant PTEN/p53 deficient murine prostate cancer via activation of neutrophil-mediated anti-tumor innate immunity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5497. doi:10.1158/1538-7445.AM2015-5497