Selected Articles from This Issue

Targeted therapies have been a breakthrough in the management of cancer. YES1, a SRC family kinase (SFK) member, has recently emerged as a druggable target in solid tumors. Here, Garmendia and colleagues review the most relevant roles and the molecular circuitry of YES1 in cancer and summarize the efficacy of SFK inhibitors in preclinical and clinical trials. YES1 is overexpressed and amplified in many solid tumors; it is also a biomarker of poor prognosis and predicts response to some SFK inhibitors. YES1 promotes tumor growth and metastasis. Available data strongly support YES1 as a novel therapeutic target in solid cancers.

Epithelial malignancies are the most commonly occurring cancers. The central involvement of protease-activated-receptors (PARs) a subgroup of G-protein coupled-receptors (GPCRs) in tumor growth and progression is becoming acknowledged. Nag and colleagues have identified a pleckstrin-homology (PH)-binding motif within PAR₄, as in PAR₁ and PAR₂ family members. A synthetic lead backbone cyclic peptide; Pc(4-4) was selected, directed toward PAR PH-binding motifs. It effectively inhibits tumor growth and attenuates activation of EGFR/erbB receptor, the most prominent cancer target. Pc(4-4) may serve as a drug not only toward PAR expressing tumors but also for EGFR/erbB tumors also in cases of resistance to traditional therapies.

Hooper and colleagues describe the generation of an antibody drug conjugate (ADC) specific for EDB+FN, an extracellular matrix protein expressed in many cancers, demonstrating safe and efficacious targeting of an ADC to a non-internalizing antigen in the tumor microenvironment – expanding the scope of druggable antigens for targeting with ADCs and other novel tumor tissue targeted modalities. Generated with site specific conjugation, EDB-ADC resulted in durable tumor regressions in mouse models without target-mediated impacts to normal tissues in non-human primate safety studies. Enhanced anti-tumor efficacy was observed when EDB-ADC was combined with anti-PD-L1 antagonist antibody, underscoring the potential to combine stromal targeting ADCs with immune checkpoint inhibitors.

Cutaneous T cell lymphoma (CTCL) is an incurable malignancy that also causes severe morbidity. Disease progression is associated with permissive changes in the immune microenvironment. Bexarotene, a common treatment for CTCL, targets cancer cells but also causes hypothyroidism that may lead to immune dysfunction. Thus, bexarotene is administered with levothyroxine which, in turn, may decrease its antineoplastic effect. Here, Cayrol and colleagues have identified in pre-clinical models a way to improve the antineoplastic effect of bexarotene plus levothyroxine replacement while maintaining cancer immunity. This mechanism involves the pharmacological inhibition of the integrin αVβ3, that is present in malignant but not normal T cells, providing a rationale for clinical testing of these compounds.