Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines
Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome – a hereditary cause of dMMR – confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability – high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy a...
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Chem. Commun., 2021, Accepted Manuscript DOI: 10.1039/D1CC03497A, CommunicationAltab Shaikh, Praveen Neeli, Gajalakshmi Singuru, Sravya Panangipalli, Raj Kumar Banerjee, M. Sridhar Reddy, Rajamannar Thennati, B. Surendar Reddy, Srigiridhar Kotamraju Herein, we document a self-assembling octyl-TPP tagged esculetin (Mito-Esc) as a functional, and as a novel small molecule siRNA delivery vector. While Mito-Esc itself induce selective breast cancer cell death,... The content of this RSS Feed (c) The Royal Society of Chemistry
In a recent note, I discused some theories about why the incidence of colonic cancer is increasing in younger patients (see:Why the Increased Incidence of Colonic Cancer Among Younger Americans?). Continuing in this same vein, a recent article I came across raised the issue of multigene panel testing to reveal genetic mutations in the roughly one-third of patents with early onset colonic cancer (see:Multigene Panel Testing Reveals Mutations in One-Third of Early Onset CRC Patients). Below is an excerpt from the article:Although the overall incidence of colorectal cancer (CRC) has been decreasing in the Unite...
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