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PCF Support Facilitates AACR Recognition Awards

April 1, 2012 -- During the American Association for Cancer Research (AACR) annual meeting, titled “Accelerating Science: Concept to Clinic,” three Prostate Cancer Foundation supported researchers were recognized for their early-career efforts in the field of prostate cancer research. The annual meeting highlights the best and latest findings in all major areas of cancer research and is designed to reflect the progress and synergy between basic, clinical and translational research that has continued to lead effective cancer therapies and prevention strategies.

Recognition Awards are given to enhance the education and training of early career scientists by providing financial support for conferences and meetings. The Prostate Cancer Foundation is proud to support the following awardees:

Lauren Geary, BS

University of Southern California, Los Angeles, CA

Title: Prostate cancer-associated fibroblasts secrete Annexin A1 that facilitates both generation of cancer stem cell-like cells (CSCs) from prostatic malignant epithelial cells and self-renewal/differentiation of CSCs

Authors: Lauren Geary, Helty Adisetiyo, Mengmeng Liang, Hyeongnam Jeong, Ebrahim Zandi, Pradip Roy-Burman. Univ. of Southern California, Los Angeles, CA

Abstract: Previously we described epithelial cell lines (Hormones & Cancer. 1: 44-54, 2010), primary cultures of cancer-associated fibroblasts (CAFs) (Cancer Res. 68: 198-205, 2008) and a primary cancer stem cell (CSC) subpopulation (Cancer Res. 70: 7294-303, 2010), all derived from the cPten-/-L mouse model of prostate adenocarcinoma (Cancer Res. 67: 7525-33, 2007). Most notably, we described evidence that CAFs secrete factors that enhance both the stemness and growth potentials of the CSCs (Cancer Res. 70: 7294-303, 2010). We have now identified the phospholipid binding Annnexin A1 as one of the pertinent secreted factors.

When a malignant epithelial cell line (cE1) derived from castration-resistant prostate cancer (CRPC) from the model was fractionated into three different subpopulations based on the levels of cell surface expression of Sca-1(S) and CD49f (C) antigens: SChi, SCme and SC- (high, medium and low expression of S and C, respectively), we found that SCme cells were preferentially susceptible to epithelial-mesenchymal transition (EMT)-like transformation when treated with conditioned medium (CM) from either CAF cultures or Annexin A1 mimetic peptide (Ac1-25). Furthermore, following EMT induction, these trans-differentiated cells acquired stem cell-like properties similar to the SChi group based on expression of S and C and statistically significant up-regulation of Oct4 (p<0.05), Sox2 (p<0.001) and Nanog (p<0.0001). When transplanted within collagen grafts under the renal capsule of Nod.Scid mice, CM- and Ac1-25-EMT-ed SCme cells were able to form invasive lesions in vivo displaying cells with expression of both basal (p63) and luminal (cytokeratin 8 ,CK8)) cell-specific markers, as compared to untreated control grafts, which lacked glandular structures and had reduced p63 positive cells.

Another effect of Annexin A1 was unraveled when CSCs (Lin- SChi subpopulation) from the primary tumors of the model were exposed to Acl-25. In vitro spheroid formation assays showed that in the presence of Acl-25 single spheroids generated from the CSCs could form multiple substructures potentially resulting from activation of additional stem-like progenitors, each capable of forming a prostasphere while remaining attached to the original spheroid structure. Immunofluorescent staining of cryosectioned spheroids revealed the presence of p63+ basal cells and an expanded population of p63/CK8 double positive transit-amplifying cells. Together these results describe two ways in which Annexin A1 may play a role in the development of a more malignant and stem cell-enriched tumor phenotype, or, to hypothetically take it a step further, possibly two ways in which Annexin A1, present in the tumor microenvironment, can lead to an increase or maintenance of a cancer stem cell(-like) population.

Ziyue Karen Jiang, BS

University of California, Los Angeles, Los Angeles, CA

Title: Monitor androgen blockade therapy with functional androgen receptor reporting system

Author: Ziyue Karen Jiang, Lily Wu. University of California, Los Angeles, Los Angeles, CA

Abstract: Hormonal manipulation remains the first line treatment for advanced prostate cancer. It includes surgical and medical means of androgen deprivation and androgen receptor (AR) blockade therapies. However, the majority of patients will develop castration resistant prostate cancer, often with metastasis that accounts for the lethality of this disease. Therefore, a reliable imaging modality capable of active surveillance of tumor recurrence and/or new incidence of metastasis would greatly benefit the timing and decision-making in adopting second line therapies. To this end, we recently constructed a prostate specific yet androgen independent promoter system, namely PSES-TSTA (Prostate Specific Enhancer Sequence coupled with Two-Step Transcriptional Amplification). We used this system to drive PET and optical imaging reporters and successfully visualized subcutaneous tumor and intra-tibial metastasis in castrated mice. The androgen independency of PSES-TSTA, which secured viability of this imaging approach when only castrated level of androgen is available, is attributed to the composition of the chimeric PSES sequence - an androgen inducible element derived from the prostate specific antigen (PSA) gene promoter and an androgen suppressible element from the prostate specific membrane antigen gene enhancer (PSME).

Another challenge faced by patients after hormonal ablation therapy is the need for effective second-line therapies. Interestingly, a growing body of evidence points out that even at castration resistant stage, AR remains active and most prostate cancer still rely on AR signaling axis for proliferation and survival. Accordingly, much effort has been devoted to the development of second generation anti-androgen agents. Therefore, it would be greatly beneficial to establish a practical and reliable reporting system that reflects the functional status of the androgen-AR axis so that the efficacy of such new drugs can be monitored at the molecular level. Inspired by previous results, we separated the two components of PSES and generated two imaging reporters: PSA-driven Firefly Luciferase (PSA-FL) and PSME-driven Renilla Luciferase (PSME-RL). Based on their respective response to androgen signaling, we anticipated that the PSA-FL signal will decrease while the PSME-RL signal will increase in the face of an effective anti-androgen therapy. Indeed, we observed such pattern of reporter gene expression in multiple prostate cancer cell lines. Importantly, this system is able to differentiate the potency and efficacy between the first generation and the more potent second generation AR antagonists. Moreover, the simultaneous application of the PSME- and PSA-driven reporter system is advantageous over the single PSA promoter-based reporter in that it rules out the effect of tumor mass reduction on the readout because both up- and down-regulation of gene expression are being assessed and imaged.

Anita G.M. Stam, BS

VU Medical Center, Amsterdam, Netherlands

Title: Activation and frequency of myeloid subsets in peripheral blood is associated with clinical outcome in prostate cancer patients treated with Prostate GVAX and anti-CTLA4
Authors: Anita G.M. Stam1, Saskia Santegoets1, Rik Scheper1, Sinéad Lougheed1, Helen Gall1, Karin Jooss2, Natalie Sacks2, Kristen Hege2, Israel Lowy3, Jean-Marie Cuillerot4, Winald Gerritsen1, Alfons van den Eertwegh1, Tanja de Gruijl1. 1VU Medical Ctr., Amsterdam, Netherlands; 2Cell Genesys Inc., San Fransisco, CA; 3Medarex, Bloomsbury, NJ; 4Bristol-Myers Squibb Company, Wallingford, CT

Abstract: Blockade of the CTLA-4 immune checkpoint can enhance anti-tumor responses and prolong survival, but it can also lead to the development of severe and potentially life-threatening immune-related adverse events (IRAE). To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity and can be used to recognize and select patients that will benefit from immune checkpoint blockade. We therefore performed extensive immune monitoring in a phase I/II dose escalation/expansion trial of combined Prostate GVAX (a GM-CSF-secreting allogeneic prostate cancer vaccine) and antiCTLA-4/ipilimumab immunotherapy in patients with Castration Resistant Prostate Cancer (CRPC). Here we report on the effects of the treatment on circulating myeloid cells and the identification of potential myeloid-related biomarkers.
The GVAX/ipilimumab combination was clinically active with PSA declines of more than 50% in 5, and PSA stabilizations in 12 of 28 patients. Regressing bone and lymph node metastasis were observed in 2/5 PR patients. Flowcytometric monitoring of myeloid subsets in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed some striking differences between patients who benefited from therapy and patients who did not. Significant treatment-induced decreases of conventional and plasmacytoid Dendritic Cell subsets (cDC and pDC, respectively) were observed, which were paralleled by increased DC activation and recruitment to the vaccination sites. Treatment-induced activation of BDCA1/CD1c+ cDC and 6-sulfo LacNAc+ inflammatory DC was associated with significantly prolonged over-all survival (OS). In contrast, increased frequencies of CD11b+CD14-CD15+ granulocytic myeloid-derived suppressor cells (MDSC) and high pre-treatment levels of CD14+HLA-DRlo/- monocytic MDSC were associated with reduced OS.

Together with similar analyses of T cell subsets, these studies have yielded an immune profile with predictive value for clinical outcome. The profile is characterized by pre- or on-treatment activation of immune effector subsets and low frequencies of regulatory/suppressive subsets. It may thus provide a potentially useful tool for patient selection and should be validated as such in other patient groups treated by antiCTLA-4 blockade.

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