Table 1.

Non-malignant diseases associated with hyperactive PI3K/mTOR signaling

Disease	Genetic defect	Targeted treatment (approved or tested)
Cowden Syndrome	PTEN haploinsufficiency	Rapalogs tested
CLOVES and other tissue overgrowth syndromes	Somatic PIK3CA mutation	Rapalogs tested; p110α inhibitors planned
APDS	Germline PIK3CD mutation	Rapalogs tested; p110δ inhibitors in trials
Tuberous sclerosis	TSC haploinsufficiency	Rapalogs approved
Lymphangioleiomyomatosis	Somatic TSC mutations	Rapalogs approved
Parkinson’s Disease	PARK2 mutations	Rapalogs *

^*In patients with early-onset Parkinson’s linked to PARK2 or alpha synuclein mutations, mTORC1 inhibition might be beneficial if treatment were started early in disease. Two potentially beneficial actions in this setting are: (1) tempering inappropriate protein synthesis and growth signaling, and (2) increasing autophagy and the clearance of neurotoxic protein aggregates.