Supraphysiologic Testosterone Induces Ferroptosis and Activates Immune Pathways through Nucleophagy in Prostate Cancer

Kumar, Rajendra; Mendonca, Janet; Owoyemi, Olutosin; Boyapati, Kavya; Thomas, Naiju; Kanacharoen, Suthicha; Coffey, Max; Topiwala, Deven; Gomes, Carolina Cavaliéri; Ozbek, Büşra; Jones, Tracy; Rosen, Marc; Dong, Liang; Wiens, Sadie; Brennen, W. Nathaniel; Isaacs, John T.; Marzo, Angelo M. De; Markowski, Mark C.; Antonarakis, Emmanuel S.; Qian, David Z.; Pienta, Kenneth J.; Pardoll, Drew M.; Carducci, Michael A.; Denmeade, Samuel R.; Kachhap, Sushant K.

doi:10.1158/0008-5472.can-20-3607

Cited by 37 publications

(26 citation statements)

References 54 publications

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“…SPA can be provided to cells as R1881, a potent synthetic androgen that is not metabolized in vitro , at a dose of 10nM, which is approximately 20-fold higher than the level of free testosterone in eugonadal adult men. LNCaP and VCaP cell lines are growth-inhibited by SPA, while LAPC4 and 22Rv1 cell lines exhibit primary resistance to SPA (Fig 1a) [1,9,10]. Among these cell lines, we observed that pre-treatment AR abundance and activity (as assessed by expression of the AR target PSA) was higher in SPA-sensitive cell lines than SPA-resistant cell lines (Fig 1b).…”

Section: Mainmentioning

confidence: 99%

“…These data suggest that SPA inhibits growth of CRPC with high AR abundance in part through downregulation of MYC. We anticipate that MYCindependent maladaptive effects of SPA may also contribute to growth inhibition, including AR inhibition of DNA relicensing during mitosis [20], AR-mediated DNA damage [21,22], and induction of ferroptosis and immunogenic cell death [10].…”

Section: Mainmentioning

confidence: 99%

“…independent maladaptive effects of SPA may also contribute to growth inhibition, including AR inhibition of DNA relicensing during mitosis [20], AR-mediated DNA damage [21,22], and induction of ferroptosis and immunogenic cell death [10].…”

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confidence: 99%

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Prostate cancer androgen receptor activity dictates efficacy of Bipolar Androgen Therapy

Sena

Kumar

Sanin

et al. 2022

Preprint

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Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), entitled Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer [1–5]. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA requires high androgen receptor (AR) abundance and activity and is driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicts downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance can be overcome by alternating SPA with the AR inhibitor enzalutamide, which induces adaptive upregulation of AR and re-sensitizes prostate cancer to SPA. This work identifies a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.

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Section: Mainmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

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Prostate cancer androgen receptor activity dictates efficacy of Bipolar Androgen Therapy

Sena

Kumar

Sanin

et al. 2022

Preprint

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“…Testosterone at supraphysiologic doses in men with CRPC has been reported to produce promising results [ 43 , 44 ], with trials suggesting a clinical benefit in a subset of patients [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Administering Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer 1–6 Days Compared to More Than 14 Days after the Start of LHRH Agonist Is Associated with Better Clinical Outcomes Due to Androgen Flare

Nasser

Sun

Scanlon

et al. 2022

Cancers

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Docetaxel, when given at the beginning of androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (MHSPC), results in significantly longer overall survival than ADT alone. We aimed to investigate if the delivery of the first dose of docetaxel during the testosterone flare associated with LHRH initiation results in better clinical outcomes, as testosterone induces mitosis of prostate cancer cells, and docetaxel specifically targets cells in mitosis. We analyzed data from the CHAARTED trial which randomized MHSPC patients to ADT alone or ADT plus docetaxel. We included only patients treated with LHRH agonist and docetaxel (n = 379). The only cutoff that resulted in differences in treatment outcomes was between patients who started docetaxel 1–6 days (n = 18) compared to more than 14 days from LHRH initiation (n = 297). Actuarial median overall survival was 72 versus 57 months (p = 0.2); progression-free survival was 49 versus 17 months (p = 0.06), and freedom from castrate-resistant prostate cancer was 51 versus 18 months (p = 0.04) for patients who started docetaxel 1–6 days compared to more than 14 days from LHRH initiation, respectively. Administering docetaxel 1–6 days from the initiation of LHRH agonist for patients with MHSPC could be associated with improved clinical outcomes.

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“…Checkpoint-blocking antibodies targeting CTLA-4, PD-1, and PD-L1 may, on the other hand, promote T cell glycolysis and IFN production by restoring pH in the TME [ 59 ]. Consequently, LDH-A increases antitumor immunity in bone marrow cells by stimulating Th17 cells to control angiogenesis and PDL1 expression; consequently, LDH-A inhibitors may provide a unique strategy for increasing the effectiveness of checkpoint inhibitors [ 60 ]. Dichloroacetate (DCA) decreases tumor cell glycolysis in melanoma [ 61 ] and also enhances the immunosuppressive state generated by lactate, hence increasing the efficacy of anticancer immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Tumor Microenvironment: Lactic Acid Promotes Tumor Development

Gao

Zhou

Liu

et al. 2022

Journal of Immunology Research

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Lactic acid is a “metabolic waste” product of glycolysis that is produced in the body. However, the role of lactic acid in the development of human malignancies has gained increasing interest lately as a multifunctional small molecule chemical. There is evidence that tumor cells may create a large amount of lactic acid through glycolysis even when they have abundant oxygen. Tumor tissues have a higher quantity of lactic acid than normal tissues. Lactic acid is required for tumor development. Lactate is an immunomodulatory chemical that affects both innate and adaptive immune cells’ effector functions. In immune cells, the lactate signaling pathway may potentially serve as a link between metabolism and immunity. Lactate homeostasis is significantly disrupted in the TME. Lactate accumulation results in acidosis, angiogenesis, immunosuppression, and tumor cell proliferation and survival, all of which are deleterious to health. Thus, augmenting anticancer immune responses by lactate metabolism inhibition may modify lactate levels in the tumor microenvironment. This review will evaluate the role of lactic acid in tumor formation, metastasis, prognosis, treatment, and histone modification. Our findings will be of considerable interest to readers, particularly those engaged in the therapeutic treatment of cancer patients. Treatments targeting the inhibition of lactate synthesis and blocking the source of lactate have emerged as a potential new therapeutic option for oncology patients. Additionally, lactic acid levels in the plasma may serve as biomarkers for disease stage and may be beneficial for evaluating therapy effectiveness in individuals with tumors.

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Supraphysiologic Testosterone Induces Ferroptosis and Activates Immune Pathways through Nucleophagy in Prostate Cancer

Cited by 37 publications

References 54 publications

Prostate cancer androgen receptor activity dictates efficacy of Bipolar Androgen Therapy

Prostate cancer androgen receptor activity dictates efficacy of Bipolar Androgen Therapy

Administering Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer 1–6 Days Compared to More Than 14 Days after the Start of LHRH Agonist Is Associated with Better Clinical Outcomes Due to Androgen Flare

Tumor Microenvironment: Lactic Acid Promotes Tumor Development

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