Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy

Narayan, Vivek; Vapiwala, Neha; Subramanian, Pearl; Christodouleas, John P.; Bekelman, Justin E.; Deville, Curtiland; Rajendran, Ramji R.; Haas, Naomi B.

doi:10.1016/j.ijrobp.2016.10.013

Cited by 20 publications

(10 citation statements)

References 31 publications

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“…However, given the frequency of minor side effects, the authors recommend a treatment dose of 5 mg/day for future studies. In a separate phase-I clinical trial, Narayan et al used radiotherapy and everolimus to treat patients with a biochemical recurrence of PC following surgery [62]. The authors concluded that this combination was feasible in patients with recurrent PC and that everolimus was well tolerated at doses below 10 mg/day.…”

Section: Adenocarcinoma Of the Prostatementioning

confidence: 99%

“…Several of these early clinical trials used mTOR inhibitors. Frequent side effects of the most commonly used mTOR inhibitor everolimus included mucositis, cutaneous rash and diarrhoea [61,62]. mTOR inhibitors were found to be safe in combination with chemotherapy and/or radiotherapy in cervical cancer, PC and rectal cancer.…”

Section: Limitations Challenges and Potential For Clinical Translationmentioning

confidence: 99%

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Radiosensitising Cancer Using Phosphatidylinositol-3-Kinase (PI3K), Protein Kinase B (AKT) or Mammalian Target of Rapamycin (mTOR) Inhibitors

Wanigasooriya

Tyler

Barros-Silva

et al. 2020

Cancers

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Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in vivo tumour xenografts and a few Phase I/II clinical trials. Most of the current evidence in this area comes from glioblastoma multiforme, non-small cell lung cancer, head and neck cancer, colorectal cancer, and prostate cancer. The biological basis for radiosensitivity following pathway inhibition was through inhibited DNA double strand break repair, inhibited cell proliferation, enhanced apoptosis and autophagy as well as tumour microenvironment changes. Dual PI3K/mTOR inhibition consistently demonstrated radiosensitisation of all types of cancer cells. Single pathway component inhibitors and other inhibitor combinations yielded variable outcomes especially within early clinical trials. There is ample evidence from preclinical studies to suggest that direct pharmacological inhibition of the PI3K/AKT/mTOR pathway components can radiosensitise different types of cancer cells. We recommend that future in vitro and in vivo research in this field should focus on dual PI3K/mTOR inhibitors. Early clinical trials are needed to assess the feasibility and efficacy of these dual inhibitors in combination with radiotherapy in brain, lung, head and neck, breast, prostate and rectal cancer patients.

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Section: Adenocarcinoma Of the Prostatementioning

confidence: 99%

Section: Limitations Challenges and Potential For Clinical Translationmentioning

confidence: 99%

Radiosensitising Cancer Using Phosphatidylinositol-3-Kinase (PI3K), Protein Kinase B (AKT) or Mammalian Target of Rapamycin (mTOR) Inhibitors

Wanigasooriya

Tyler

Barros-Silva

et al. 2020

Cancers

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“…Everolimus, a derivative of Sirolimus, was FDA approved (2009) for the prevention of organ transplant rejection and for the treatment of multiple tumor types (renal cell, giant cell astrocytoma, and pancreatic neuroendocrine tumors) ( , accessed on 24 August 2021). Three studies have been published using a combination of Everolimus and radiotherapy, with the two Phase 1 studies showing a safe side effect profile [ 71 , 72 ] and the one completed Phase 2 trial showing no benefit to the addition of Everolimus to temozolomide and radiation in patients with glioblastoma [ 22 ]. The last mTORC1 specific drug, Ridaforolimus, had a positive Phase 3 trial in soft tissue sarcoma, but no studies are ongoing in combination with radiotherapy ( , accessed on 24 August 2021).…”

Section: Signaling Molecules Regulating Eif4f Activitymentioning

confidence: 99%

Translation Initiation Machinery as a Tumor Selective Target for Radiosensitization

Lehman

Wilson

Camphausen

et al. 2021

IJMS

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Towards improving the efficacy of radiotherapy, one approach is to target the molecules and processes mediating cellular radioresponse. Along these lines, translational control of gene expression has been established as a fundamental component of cellular radioresponse, which suggests that the molecules participating in this process (i.e., the translational machinery) can serve as determinants of radiosensitivity. Moreover, the proteins comprising the translational machinery are often overexpressed in tumor cells suggesting the potential for tumor specific radiosensitization. Studies to date have shown that inhibiting proteins involved in translation initiation, the rate-limiting step in translation, specifically the three members of the eIF4F cap binding complex eIF4E, eIF4G, and eIF4A as well as the cap binding regulatory kinases mTOR and Mnk1/2, results in the radiosensitization of tumor cells. Because ribosomes are required for translation initiation, inhibiting ribosome biogenesis also appears to be a strategy for radiosensitization. In general, the radiosensitization induced by targeting the translation initiation machinery involves inhibition of DNA repair, which appears to be the consequence of a reduced expression of proteins critical to radioresponse. The availability of clinically relevant inhibitors of this component of the translational machinery suggests opportunities to extend this approach to radiosensitization to patient care.

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“…So far, much of the clinical focus towards mTOR inhibition has revolved around sirolimus (rapamycin) and its analogues everolimus (RAD001) and temsirolimus (CCI-779). However, despite showing good tolerability profiles when used alone or combined with other treatments, little anti-tumor activity has been reported in the clinic [ 40 , 41 , 42 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 ]. Efforts to improve the bioavailability and performance of these agents through nanoparticle encapsulation and binding are ongoing, although whether this improves their anti-tumor effects remains to be determined [ 250 , 251 ].…”

Section: Targeting Pten-deficient Prostate Cancermentioning

confidence: 99%

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

Turnham

Bullock

Dass

et al. 2020

Cells

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Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K–AKT–mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K–AKT–mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.

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Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy

Cited by 20 publications

References 31 publications

Radiosensitising Cancer Using Phosphatidylinositol-3-Kinase (PI3K), Protein Kinase B (AKT) or Mammalian Target of Rapamycin (mTOR) Inhibitors

Radiosensitising Cancer Using Phosphatidylinositol-3-Kinase (PI3K), Protein Kinase B (AKT) or Mammalian Target of Rapamycin (mTOR) Inhibitors

Translation Initiation Machinery as a Tumor Selective Target for Radiosensitization

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

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