CD8+ T cells specific for the androgen receptor are common in patients with prostate cancer and are able to lyse prostate tumor cells

324 Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new therapeutics are urgently needed. Prostate specific membrane antigen (PSMA) is expressed on the surface of prostate cancer cells and expression increases with disease progression. Therapies directed against PSMA such as radiolabeled antibodies and T cell redirecting therapies including chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs) have shown promising efficacy in clinical trials but also induce significant toxicity. In particular CAR-Ts and T-BsAbs potently kill tumor cells but induce cytokine release-related toxicities. Novel anti-CD3 engaging domains may be required to create T-BsAbs with a broader therapeutic window. We have developed fully human CD3xPSMA bispecific antibodies that efficiently eliminate prostate tumor cells while minimizing cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated in transgenic rats that produce human antibodies (UniRat, OmniFlic) followed by repertoire deep sequencing of lymph nodes isolated from immunized animals and high-throughput gene assembly/expression. CD3xPSMA T-BsAbs were assembled and evaluated for T cell activation and ability to eliminate PSMA+ tumor cells in vitro. Results: Primary human T cells were activated only in the presence of both bispecific CD3xPSMA antibodies and PSMA (either plate-bound or on the surface of tumor cells). Potent and selective cytotoxicity against PSMA+ prostate tumor cells was observed in co-cultures of primary human T cells and tumor cells treated with CD3xPSMA bispecific antibodies. Strikingly, CD3xPSMA bispecifics containing a novel low affinity anti-CD3 domain produced similar levels of tumor cell cytotoxicity compared to CD3xPSMA bispecifics containing a traditional high affinity anti-CD3 domain, but with reduced cytokine production. Conclusions: We have created novel CD3xPSMA bispecific antibodies that mediate T-cell killing of PSMA+ tumor cells with minimal production of cytokines. Such T-BsAbs may improve safety, efficacy, and opportunities for combination therapy to treat CRPC.

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Unexpected paracrine action of prostate cancer cells harboring a new class of androgen receptor mutation—A new paradigm for cooperation among prostate tumor cells

International Journal of Cancer ◽

10.1002/ijc.22830 ◽

2007 ◽

Vol 121 (6) ◽

pp. 1238-1244 ◽

Cited By ~ 24

Author(s):

Gaëlle Lapouge ◽

Eva Erdmann ◽

Gemma Marcias ◽

Monika Jagla ◽

Audrey Monge ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Tumor Cells ◽

Prostate Tumor ◽

Prostate Cancer Cells ◽

New Paradigm ◽

New Class ◽

Paracrine Action ◽

Prostate Tumor Cells

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The secreted matrix protein mindin increases prostate tumor progression and tumor-bone crosstalk via ERK 1/2 regulation

Carcinogenesis ◽

10.1093/carcin/bgz105 ◽

2019 ◽

Vol 40 (7) ◽

pp. 828-839

Author(s):

Juan A Ardura ◽

Irene Gutiérrez-Rojas ◽

Luis Álvarez-Carrión ◽

M Rosario Rodríguez-Ramos ◽

José M Pozuelo ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Progression ◽

Tumor Cells ◽

Matrix Protein ◽

Bone Cells ◽

Prostate Tumor ◽

Dependent Manner ◽

Prostate Tumors ◽

Adenocarcinoma Cells ◽

Prostate Tumor Cells

Abstract Advanced prostate cancer cells preferentially metastasize to bone by acquiring a bone phenotype that allows metastatic cells to thrive in the skeletal environment. Identification of factors that promote the expression of ectopic bone genes—process known as osteomimicry—leading to tumor progression is crucial to prevent and treat metastatic prostate cancer and prolong life expectancy for patients. Here, we identify the extracelular matrix protein mindin in the secretome of prostate adenocarcinoma cells and show that mindin overexpression in human and mouse TRAMP-C1-induced prostate tumors correlates with upregulated levels of bone-related genes in the tumorigenic prostate tissues. Moreover, mindin silencing decreased osteomimicry in adenocarcinoma cells and in the prostate tumor mice model, as well as reduced tumor cell proliferation, migration and adhesion to bone cells. Inhibition of the extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation decreased the proliferative, migratory and pro-adhesion actions of mindin on prostate tumor cells. In addition, conditioned media obtained by crosstalk stimulation of either osteocytes or osteoblasts with the secretome of TRAMP-C1 cells promoted osteomimicry in prostate tumor cells; an effect inhibited by mindin silencing of TRAMP-C1 cells. In vivo, tibiae of primary tumor-bearing mice overexpressed the pro-angiogenic and pro-metastattic factor vascular endothelial growth factor receptor 2 (VEGFR2) in a mindin-dependent manner. Our findings indicate that mindin is a novel regulator of osteomimicry in prostate tumors and potentially mediates tumor-bone cell crosstalk, suggesting its promising role as a target to inhibit bone metastases.

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A nonlinear model with competition between prostate tumor cells and its application to intermittent androgen suppression therapy of prostate cancer

Mathematical Biosciences ◽

10.1016/j.mbs.2008.03.001 ◽

2008 ◽

Vol 214 (1-2) ◽

pp. 134-139 ◽

Cited By ~ 36

Author(s):

Takashi Shimada ◽

Kazuyuki Aihara

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Nonlinear Model ◽

Prostate Tumor ◽

Intermittent Androgen Suppression ◽

Androgen Suppression ◽

Prostate Tumor Cells

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Role of androgen receptor in the progression of human prostate tumor cells to androgen independence and insensitivity

The Prostate ◽

10.1002/pros.20285 ◽

2005 ◽

Vol 65 (4) ◽

pp. 287-298 ◽

Cited By ~ 42

Author(s):

John M. Kokontis ◽

Stephen Hsu ◽

Chih-pin Chuu ◽

Mai Dang ◽

Junichi Fukuchi ◽

...

Keyword(s):

Androgen Receptor ◽

Tumor Cells ◽

Prostate Tumor ◽

Human Prostate ◽

Androgen Independence ◽

Prostate Tumor Cells ◽

Human Prostate Tumor

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Unbiased Phenotype-Based Screen Identifies Therapeutic Agents Selective for Metastatic Prostate Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.594141 ◽

2021 ◽

Vol 10 ◽

Author(s):

Ivy Chung ◽

Kun Zhou ◽

Courtney Barrows ◽

Jacqueline Banyard ◽

Arianne Wilson ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Metastatic Prostate Cancer ◽

Prostate Tumor ◽

Prostate Cancer Cells ◽

Normal Prostate ◽

Prostate Tumor Cells ◽

Benign Prostate

In American men, prostate cancer is the second leading cause of cancer-related death. Dissemination of prostate cancer cells to distant organs significantly worsens patients’ prognosis, and currently there are no effective treatment options that can cure advanced-stage prostate cancer. In an effort to identify compounds selective for metastatic prostate cancer cells over benign prostate cancer cells or normal prostate epithelial cells, we applied a phenotype-based in vitro drug screening method utilizing multiple prostate cancer cell lines to test 1,120 different compounds from a commercial drug library. Top drug candidates were then examined in multiple mouse xenograft models including subcutaneous tumor growth, experimental lung metastasis, and experimental bone metastasis assays. A subset of compounds including fenbendazole, fluspirilene, clofazimine, niclosamide, and suloctidil showed preferential cytotoxicity and apoptosis towards metastatic prostate cancer cells in vitro and in vivo. The bioavailability of the most discerning agents, especially fenbendazole and albendazole, was improved by formulating as micelles or nanoparticles. The enhanced forms of fenbendazole and albendazole significantly prolonged survival in mice bearing metastases, and albendazole-treated mice displayed significantly longer median survival times than paclitaxel-treated mice. Importantly, these drugs effectively targeted taxane-resistant tumors and bone metastases – two common clinical conditions in patients with aggressive prostate cancer. In summary, we find that metastatic prostate tumor cells differ from benign prostate tumor cells in their sensitivity to certain drug classes. Taken together, our results strongly suggest that albendazole, an anthelmintic medication, may represent a potential adjuvant or neoadjuvant to standard therapy in the treatment of disseminated prostate cancer.

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