Cole et al. Page 483

Prostate cancer is the most frequently diagnosed cancer and second leading cause of cancer death in US males. Androgen receptor (AR) is the best-known therapeutic target for prostate cancer. Here, Cole and colleagues have identified a novel small molecule, (+)-JJ-74-138, that directly binds to the AR and non-competitively inhibits AR activity. Furthermore, this small molecule shows efficacy in vitro and in vivo in models resistant to clinically available AR antagonists that competitively inhibit the binding of androgens to AR. Further development of non-competitive AR antagonists like (+)-JJ-74-138 shows promise treating tumors resistant to current AR targeting therapies.

Spiliopoulou et al. Page 522

Epigenetic modulation has recently emerged as an immune evasion mechanism in cancer. The co-dependence of G9A and EZH2 histone methyltransferases in regulating gene transcription led to the development of the dual G9A/EZH2 inhibitor, HKMTI-1-005. In this highlighted manuscript, Spiliopoulou and colleagues demonstrate that treatment with HKMTI-1-005 derepresses transcription of immunostimulatory gene networks and achieves robust engraftment of tumor-infiltrating lymphocytes in the Trp53‒/‒ ID8 mouse model of ovarian cancer. Immune infiltration was accompanied by tumor growth inhibition and an improvement in survival. Collectively these results support further development of epigenetic modifiers as an anti-cancer strategy.

Li et al. Page 535

The high mortality of PDAC attributes to early metastasis at diagnosis and chemoresistance partly driven by mutant p53. PDAC cells are predisposed to ferroptosis. New therapeutics capable of inducing ferroptosis and inhibiting PDAC metastasis are highly desirable. This study by Li, et al reports a small molecule compound MMRi62 bearing these two capabilities. This study shows MMRi62 inhibits PDAC proliferation in vitro and in vivo by induction of ferroptosis via induced lysosomal degradation of ferritin heavy chain and inhibits metastasis in vivo which involves proteasomal degradation of mutant p53.

Zammarchi et al. Page 582

Zammarchi and colleagues describe the development of ADCT-601, a novel pyrrolobenzodiazepine dimer-based antibody-drug conjugate targeting AXL, a well-known tyrosine kinase receptor implicated in numerous aspects of tumor development, progression, and resistance to cancer therapies. Zammarchi and colleagues present original data outlining the mode of action of ADCT-601 when used as monotherapy, both in vitro and in vivo, in tumor models of different origins, including a monomethyl auristatin E-resistant lung cancer model, and in combination with olaparib in an ovarian cancer model; preclinical evaluation of its safety and tolerability is also reported. Altogether, the data presented warrant further evaluation of ADCT-601 in the clinical setting.