MCT First Disclosures

FolRα is a cell-surface glycoprotein that is frequently over-expressed in multiple cancer indications including ovarian and endometrial cancers, which are the most lethal cancers for female reproductive system. Here we reported the discovery of STRO-002, a homogeneous antibody-drug-conjugate (ADC) that binds to FolRα with high affinity, internalizes, and releases a novel tubulin-targeting cytotoxin (hemiasterlin) to kill FolRα expressing tumor cells. With superior stability and favorable pharmacokinetic (PK) profile, a single dose of STRO-002 induced significant tumor growth inhibition in xenograft and PDX models. Phase I studies for STRO-002 are in progress in ovarian and endometrial cancer patients (NCT03748186 and NCT05200364).

Nectin-4 is a validated cancer target through ADC enfortumab vedotin. Rigby and colleagues have identified BT8009, a Bicycle® Toxin Conjugate that selectively binds Nectin-4 providing robust activity, and affording similar, or improved, activity over an ADC based on enfortumab vedotin, in several pre-clinical xenograft cancer models. The small, hydrophilic, nature of BT8009 results in a pharmacokinetic profile very different from an ADC, with a high Cmax, rapid extravasation from systemic circulation and rapid renal elimination. These different physical and PK characteristics may provide benefit for tumor penetration and reduced systemic exposure. BT8009 is in an ongoing Phase 1/2 clinical trial.

The oncogenic transcription factor C/EBPβ is an emerging therapeutic target for many cancers. Rotolo and colleagues present data describing ST101, a peptide antagonist that prevents C/EBPβ dimerization and enhances its proteasome-dependent degradation. ST101 attenuates C/EBPβ target gene expression, resulting in tumor-specific cytotoxicity in glioblastoma, breast, melanoma, prostate, and lung cancer cells, while normal human epithelial cells are not impacted. In vivo xenograft models indicate that ST101 induces potent tumor growth inhibition or regression, both as a single agent and in combination studies. These data identify ST101 as a promising therapeutic against C/EBPβ-dependent cancers.

Glioblastoma (GBM) is one of the most aggressive cancers and it is usually refractory to immunotherapies. EGFR variant III (EGFRvIII) is an EGFR mutation commonly present in GBM that generates a unique cell surface neoantigen in tumor cells. Here, Iurlaro and colleagues have designed and developed a novel T cell bispecific antibody (TCB) with specificity for EGFRvIII and CD3. The EGFRvIII-TCB promoted T cell activation and tumor cell killing in EGFRvIII-expressing patient-derived models, and induced tumor regression in GBM patient-derived xenografts (PDX). These results led to the clinical testing of the EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

The IDO1/TDO2-AHR pathway drives immunosuppressive tumor microenvironments and high pathway activity is correlated with poor prognosis in many cancer types. AHR is a transcription factor activated by kynurenine and other ligands and is an ideal therapeutic target for reversing the broad immunosuppressive activities mediated by this pathway. McGovern and colleagues introduce IK-175, a selective small molecule that inhibits AHR in vitro and in vivo. IK-175 inhibits tumor growth alone and combined with anti-PD-1 antibodies and reverses immune suppression and increases pro-inflammatory cytokines and effector immune cells in preclinical tumor models. These data provide rationale treating cancer patients with IK-175.

Active mutations in epidermal growth factor receptor (EGFR) are found in about 15% of Caucasian and 30–40% of Asian patients with advanced non-small-cell lung cancer (NSCLC). Currently there are no effective treatment options for NSCLC patients with osimertinib-resistant EGFR triple mutations. Here, Yong Du and coworkers report an orally bioavailable EGFR PROTAC, HJM-561, which selectively degrades EGFR C797S triple mutants with robust in vivo efficacy. This study provides a therapeutic option for treating osimertinib-resistant NSCLC patients and also suggests that targeted protein degradation is very promising to resolve drug resistance in cancer therapy.

Scribner and colleagues leveraged two platforms – an intact tumor cell immunization target discovery platform and a maytansine-based linker-drug platform – to identify cancer targets and develop ADCs against these targets. Antibodies to ADAM9 were generated with properties amenable to an ADC approach - among them, strong tumor-to-normal tissue binding differential and efficient internalization/processing by tumor cells. IMGC936, generation maytansine payload, was developed. IMGC936 exhibits potent antitumor activity in human CDX/PDX models and an acceptable safety profile in primates. The data supports initiation of a first-in-human study of IMGC936 in patients with solid tumors.

Ataxia telangiectasia mutated (ATM) kinase controls key cell cycle checkpoints and the repair of DNA double strand breaks and has been considered an attractive intervention point in DNA damage response for cancer therapy. Here, Zimmermann et al. introduce two novel ATM inhibitors. These highly potent and selective small molecules effectively suppress the ATM pathway, enhance antitumor effect of radiation and topoisomerase I inhibitors and synergize with PARP inhibitors in cancer cells and animal models of human cancer. They represent new molecular tools with potential for combination with key cancer therapies.

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.

Histone deacetylases (HDACs) play a critical role in epigenomic regulation of cancer cell signaling. HDAC inhibitors to-date have faced challenges due to poor isoform selectivity and narrow therapeutic indices. In this first disclosure, Diamond and colleagues report the discovery and preclinical development of the novel, orally bioavailable, class I-targeting HDAC inhibitor, OKI-179 (NCT03931681). OKI-179 was active against solid tumors in preclinical cancer models with a favorable pharmacokinetic profile and on-target pharmacodynamic effects. OKI-179 is a promising next generation HDAC inhibitor suitable for combining with other targeted agents based on its potency, desirable class I HDAC inhibition profile and oral bioavailability.

ATR is essential to protect genome integrity during DNA replication in cancer cells. In this first disclosure, Roulston and colleagues identify RP-3500 (NCT04497116), a highly potent and selective oral ATR inhibitor with efficacy as a monotherapy and in combination with PARP inhibitors in several xenograft models. Preclinically, intermittent dosing of RP-3500 maintains efficacy without inducing anemia, a dose-limiting toxicity observed clinically for ATR inhibitors. Furthermore, concurrent administration of RP-3500 with PARP inhibitors on an intermittent schedule provides greater efficacy and reduced toxicity compared to sequential administration, providing an opportunity to maximize clinical benefit for this class of anti-cancer agent.

PRMT5 over-expression occurs in multiple cancer types, including non-small cell lung cancer (NSCLC). PRMT5 inhibition generates intron retention and exon skipping, resulting in promotion of apoptosis. Mutations conferring drug resistance have challenged previous SAM-cooperative PRMT5 inhibitors entering clinical trials. In this First Disclosure, Jensen-Pergakes and colleagues identify PF-06939999, a SAM-competitive PRMT5 inhibitor, through a structure-based design. Analysis of acquired resistance to SAM-cooperative and SAM-competitive PRMT5 inhibition suggested the latter may be less susceptible to complete drug resistance. PF-06939999 demonstrated anti-proliferative activity in NSCLC tumors with multiple pathways downregulated. Their results support the clinical development of PF-06939999 in splicing dysregulated NSCLC.