Selected Articles from This Issue

Abstract

Inhibition of DNA damage response and PI3K signaling has emerged as a potential strategy for treating triple-negative breast cancer (TNBC). Hong and colleagues assessed a CHK1 inhibitor, prexasertib, in combination with a PI3K/mTOR inhibitor, samotolisib, in preclinical models and a phase Ib study. This combination was synergistic or additive in 30 of 38 PDX models examined. In the clinical setting, an overall response rate (ORR) of 15.1% was observed. However, the toxicity profile of this combination limits its utility moving forward. Given the potential clinical benefit of the combined inhibition of CHK1 and PI3K/mTOR, alternative strategies to more safely target these pathways in patients are needed.Although immune checkpoint inhibition has provided clinical benefit to cancer patients, many patients do not ultimately respond to this strategy; thus, new strategies to enhance the efficacy of ICI are needed. Papadopoulos and colleagues performed a phase I study of an anti-GITR monoclonal antibody, MK-4166, as monotherap. and in combination with pembrolizumab in patients with advanced solid tumors. MK-4166 was well tolerated, and a maximum-tolerated dose was not reached. Clinical responses were observed with combination treatment, particularly in patients with ICI-naïve melanoma, with an ORR of 62%. Further study of this combination is warranted, particularly in patients not previously treated with ICI.The T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed by tumor-infiltrating lymphocytes (TILs) and has emerged as an attractive target for checkpoint blockade therapies. Shaffer and colleagues developed a novel PET imaging to noninvasively quantify TIGIT expression in the tumor microenvironment. The probe was highly specific for TIGIT expressed by TILs in syngeneic mouse melanoma models as demonstrated with small animal PET imaging, ex vivo flow cytometry, and immunofluorescence microscopy. This TIGIT imaging probe shows promise as the basis of a clinically relevant tool in screening cancer patients and monitoring therapeutic efficacy.Inherited mutations in DNA repair genes commonly are associated with familial cancer. Using MSK-IMPACT, Topka and colleagues identified a subset of patients with cancer-harboring germline or somatic aberrations within the nucleotide excision repair (NER) pathway, including ERCC2 and ERCC3. Cells harboring heterozygous mutations in these genes showed increased sensitivity to irofulven. Synergy was identified between irofulven and several additional therapeutics, including cisplatin. These data suggest that further study of irofulven is warranted, especially in ERCC2/3-mutant patients.