Exceptional Response to Everolimus in a Patient with Metastatic Castrate-Resistant Prostate Cancer Harboring a PTEN Inactivating Mutation
Jamie A. Kmaka Nikita Agarwala Yuting Hea Andreas M. Heilmanna Vincent A. Millera Jeffrey S. Rossa, b Sumanta Kumar Palc Siraj M. Alia Deepak Kilaric
aFoundation Medicine, Cambridge, MA, USA; bDepartment of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; cDepartment of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
Prostate cancer is among the most common types of cancer in men. Early detection and proper medical intervention is crucial to ensuring successful treatment. Here we describe a patient clinically presenting with castrate-resistant prostate carcinoma. Comprehensive ge- nomic profiling identified a PTEN inactivating mutation in the patient’s tumor. After being heavily pretreated, the patient showed stable disease on everolimus, a PI3K-Akt-mTOR path- way inhibitor.
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However, one mCRPC trial was ended due to "clinical futility":
"Everolimus demonstrated predictable toxicity in advanced and heavily pretreated patients with mCRPC. No clinical or clear pathologic effects despite downstream TORC1 target inhibition, suggesting that single agent everolimus has no clinical utility in men with mCRPC."
Included men with "progressive CRPC with serum testosterone levels <50 ng/dL. No prior bicalutamide (except to prevent flare)"
"The combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide-naive CRPC, thus warranting further investigation. A substantial number of patients experienced everolimus-related toxicity."
"mTOR Complex 1 (mTORC1) is composed of mTOR ..." [1].
{not to be confused with TORC1, the Transducer Of Regulated CREB activity 1. [2]}
Rapamycin was discovered on Rapa Nui (Easter Island). In time a human protein was discovered that responded to it, so they called it the mammalian target of rapamycin [mTOR].
"Compared with the parent compound rapamycin, Everolimus is more selective for the mTORC1 protein complex, with little impact on the mTORC2 complex"
Everolimus is approved for breast cancer. In the studies with prostate cancer, high toxicity and sometimes limited benefit against PCa is reported, if patients were not selected for PTEN loss. Here are links to some prostate cancer studies with Everolimus:
Yes it is pretty toxic. It's use has to be closely monitored. It is an immune suppressant and is often used to prevent organ transplant rejection. This is why I was interested in it. I have a kidney transplant and take the drug Tacrolimus as an immune suppressant.
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1/4 dose enzalutamide for MCRPc working for 4 years in 87 yr. old
promising against soft tissue and bone metastasis: AMG 509
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