The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many open questions regarding tolerability, patient selection, sensitivity markers, development of resistances, and toxicological challenges still need to be addressed. Besides clear oncological indications, PI3K and mTOR inhibitors have been suggested for treating a plethora of different diseases. In particular, genetically induced PI3K/mTOR pathway activation causes rare disorders, known as overgrowth syndromes, like PTEN (phosphatase and tensin homolog) hamartomas, tuberous sclerosis complex (TSC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS), and activated PI3-Kinase delta syndrome (PI3KCD, APDS). Some of those disorders likeTSC or hemimegalencephaly, which are one of the PROS disorders, also belong to a group of diseases called mTORopathies. This group of syndromes presents with additional neurological manifestations associated with epilepsy and other neuropsychiatric symptoms induced by neuronal mTOR pathway hyperactivation. While PI3K and mTOR inhibitors have been and still are intensively tested in oncology indications, their use in genetically defined syndromes and mTORopathies appear to be promising avenues for a pharmacological intervention.

https://www.mdpi.com/1422-0067/20/22/5792/pdf

PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases.

• Age-associated B cells (ABCs) are considered as drivers of autoimmune disease pathogenesis. • SWEF proteins (DEF6 and SWAP-70) regulate ABCs, via a mechanism involving IRF5 and IL-21. • Lack of DEF6 and/or SWAP-70 leads to increased Rho-kinase (ROCK) activity in immune cells. • ROCK inhibitors may deplete ABCs, thus contribute to autoimmune disease management and therapy. 

Rho-kinase inhibitors to deplete age-associated B cells in systemic autoimmunity

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

The understanding of molecular mechanisms of cancer biology has greatly increased over the past decade. Additional hallmarks of cancer, such as immune tolerance and deregulation of cellular energetics, have been recognized. Targeted cancer therapy aims to interfere with every hallmark of cancer. Potential novel targets are constantly being identified and evaluated. Novel cancer therapeutics that are efficacious in a subset of tumors are on their way to the clinic. Biomarker strategies for patient stratification and evaluation of patient benefit are critical for the efficient use of these personalized medicines. This article gives an overview of different fields of targeted cancer drug discovery and strategies to validate novel targets and biomarkers.

Cancer Biology and the Principles of Targeted Cancer Drug Discovery

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Cancer Biology and the Principles of Targeted Cancer Drug Discovery