Enhanced radiosensitization of enzalutamide via schedule dependent administration to androgen‐sensitive prostate cancer cells

Ghashghaei, Maryam; Paliouras, Miltiadis; Heravi, Mitra; Bekerat, Hamed; Trifiro, Mark; Niazi, Tamim; Muanza, Thierry

doi:10.1002/pros.23445

Cited by 43 publications

(47 citation statements)

References 53 publications

(112 reference statements)

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“…In addition, pre-treatment with ENZ led to more profound DNA damage (phospho-γH2A.X foci) compared to RLT alone. This is in line with in vitro studies reporting that treatment with ENZ combined with irradiation [ 15 , 16 ] or the p oly ( A DP- R ibose) p olymerase inhibitor olaparib [ 17 ] increased the number of phospho-γH2A.X foci resulting from either treatment (X-ray or olaparib) alone.…”

Section: Discussionsupporting

confidence: 86%

Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

et al. 2018

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BackgroundProstate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a promising yet not curative approach in castration-resistant (CR) prostate cancer (PC). Rational combination therapies may improve treatment efficacy. Here, we explored the effect of androgen receptor blockade (ARB) on PSMA expression visualized by PET and its potential additive effect when combined with 177Lu-PSMA RLT in a mouse model of prostate cancer.MethodsMice bearing human CRPC (C4-2 cells) xenografts were treated with 10 mg/kg enzalutamide (ENZ), with 50 mg/kg bicalutamide (BIC), or vehicle (control) for 21 days. PSMA expression was evaluated by 68Ga-PSMA11 PET/CT and quantified by flow cytometry of tumor fine needle aspirations before treatment and on days 23, 29, 34, and 39 post-therapy induction. For the RLT combination approach, mice bearing C4-2 tumors were treated with 10 mg/kg ENZ or vehicle for 21 days before receiving either 15 MBq (84 GBq/μmol) 177Lu-PSMA617 or vehicle. DNA damage was assessed as phospho-γH2A.X foci in tumor biopsies. Reduction of tumor volume on CT and survival were used as study endpoints.ResultsTumor growth was delayed by ARB while 68Ga-PSMA11 uptake increased up to 2.3-fold over time when compared to controls. ABR-induced upregulation of PSMA expression was confirmed by flow cytometry. Phospho-γH2A.X levels increased 1.8- and 3.4-fold at 48 h in response to single treatment ENZ or RLT and ENZ+RLT, respectively. Despite significantly greater DNA damage and persistent increase of PSMA expression at the time of RLT, no additional tumor growth retardation was observed in the ENZ+RLT group (vs. RLT only, p = 0.372 at day 81). Median survival did not improve significantly when ENZ was combined with RLT.ConclusionARB-mediated increases in PSMA expression in PC xenografts were evident by 68Ga-PSMA11 PET imaging and flow cytometry. 177Lu-PSMA617 effectively decreased C4-2 tumor size. However, while pre-treatment with ARB increased DNA damage significantly, it did not result in synergistic effects when combined with RLT.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0451-z) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 86%

Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

et al. 2018

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“…Radiotherapy has been shown to induce AR expression in prostate cancer cells, and ADT sensitizes cancer cells to radiotherapy 198 . Treatment with enzalutamide was also shown to radiosensitize prostate cancer cells more effectively than ADT 199 . Combination treatment with enzalutamide and radiation therapy resulted in a significant increase in apoptosis and senescence compared to treatment with enzalutamide or radiation alone 199 .…”

Section: Combination Therapies Ar + Radiation Therapymentioning

confidence: 99%

“…Treatment with enzalutamide was also shown to radiosensitize prostate cancer cells more effectively than ADT 199 . Combination treatment with enzalutamide and radiation therapy resulted in a significant increase in apoptosis and senescence compared to treatment with enzalutamide or radiation alone 199 . In prostate cancer, radiosensitization was also observed with ARN-509 97 .…”

Section: Combination Therapies Ar + Radiation Therapymentioning

confidence: 99%

ARe we there yet? Understanding androgen receptor signaling in breast cancer

et al. 2020

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The role of androgen receptor (AR) activation and expression is well understood in prostate cancer. In breast cancer, expression and activation of AR is increasingly recognized for its role in cancer development and its importance in promoting cell growth in the presence or absence of estrogen. As both prostate and breast cancers often share a reliance on nuclear hormone signaling, there is increasing appreciation of the overlap between activated cellular pathways in these cancers in response to androgen signaling. Targeting of the androgen receptor as a monotherapy or in combination with other conventional therapies has proven to be an effective clinical strategy for the treatment of patients with prostate cancer, and these therapeutic strategies are increasingly being investigated in breast cancer. This overlap suggests that targeting androgens and AR signaling in other cancer types may also be effective. This manuscript will review the role of AR in various cellular processes that promote tumorigenesis and metastasis, first in prostate cancer and then in breast cancer, as well as discuss ongoing efforts to target AR for the more effective treatment and prevention of cancer, especially breast cancer.

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“…Notably, multiple solid tumor cell lines have shown dose-dependent cellular senescence induction in response to DNA damaging agents such as doxorubicin, diaziquone, cisplatin, and to a lesser degree ionizing radiation. Recently reported data suggest enzalutamide, an antiandrogen, potentiates DNA damage caused by radiation and significantly increases radiation-induced cellular senescence in LNCaP cells [26] .…”

Section: Cellular Senescence As a Response To Adt In Pcamentioning

confidence: 99%

Combination therapy with androgen deprivation for hormone sensitive prostate cancer: A new frontier

Etheridge

Damodaran

Schultz

et al. 2019

Asian Journal of Urology

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Androgen deprivation therapy (ADT) has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer (PCa). However, this approach is rarely curative. Recent clinical trials have demonstrated that ADT combined with other agents, notably docetaxel and abiraterone, lead to improved survival. The mechanisms surrounding this improved cancer outcomes are incompletely defined. The response of cancer cells to ADT includes apoptosis and cell death, but a significant fraction remains viable. Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells. Cellular senescence is a phenotype characterized by cell cycle arrest, senescence-associated β-galactosidase (SA-β-gal), and a hypermetabolic state. Positive features of cellular senescence include growth arrest and immune stimulation, although persistence may release cytokines and growth factors that are detrimental. Senescent tumor cells generate a catabolic state with increased glycolysis, protein turnover and other metabolic changes that represent targets for drugs, like metformin, to be applied in a synthetic lethal approach. This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.

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Enhanced radiosensitization of enzalutamide via schedule dependent administration to androgen‐sensitive prostate cancer cells

Cited by 43 publications

References 53 publications

Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

ARe we there yet? Understanding androgen receptor signaling in breast cancer

Combination therapy with androgen deprivation for hormone sensitive prostate cancer: A new frontier

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