On April 8, 2024 Accent Therapeutics, a biopharmaceutical company pioneering a novel class of small molecule precision cancer therapeutics reported advances in cancer targeting, including data on DHX9 and KIF18A inhibitor activity in multiple tumor types, at the 2024 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 5-10 in San Diego, California (Press release, Accent Therapeutics, APR 8, 2024, View Source [SID1234641888]).
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"Accent has expanded the potential of our two lead programs in preclinical investigations, and we are excited for the promise they hold for addressing cancers with high unmet clinical need," said Robert A. Copeland, Ph.D., President, Founder, and Chief Scientific Officer of Accent Therapeutics. "Our results reveal that DHX9 and KIF18A inhibition are potent therapeutic strategies that stand to benefit large patient populations. These findings validate our systematic approach to tapping the rich therapeutic potential of our target space."
In the presentation entitled "RNA-Modifying Enzyme Inhibitors as Precision Cancer Therapeutics," Dr. Copeland delineates the promise of RNA-modifying enzyme (RME) inhibitors as precision cancer therapeutics that confer cancer-selective growth inhibition in vitro and in vivo. The potential of RME inhibitors is exemplified by inhibitors of the novel cancer target, DHX9, which display great promise as a novel treatment modality in BRCA1 and/or BRCA2 loss-of-function (LOF) cancers across multiple tumor types, including breast cancers.
Studies in breast cancer models demonstrate the potential impact of DHX9 inhibitor treatment for patients with defective DNA repair. These data are highlighted in a presentation entitled "DHX9 inhibition as a novel therapeutic for cancer with loss-of-function mutations in DNA damage repair genes BRCA1 and BRCA2." Additional key takeaways from this talk are:
DHX9 inhibition shows selective growth inhibition in breast cancer cell lines that exhibit BRCA LOF
DHX9 inhibition results in DNA damage and catastrophic increase in replication stress in BRCA LOF cell lines, causing cell cycle arrest prior to onset of apoptosis
In vivo, DHX9 inhibitors were well tolerated and demonstrate robust tumor growth inhibition in multiple BRCA LOF cell line xenograft models
Accent scientists further reinforce KIF18A – a kinesin that plays a critical role in facilitating mitosis – as a compelling therapeutic target in chromosomally instable tumors. In a poster entitled "Inhibition of KIF18A leads to mitotic arrest and robust anti-tumor activity in chromosomally instable tumors," they show data that Accent’s novel, potent and selective small molecule inhibitors of KIF18A:
Upregulate biomarker proteins, indicating specific induction of mitotic arrest, DNA damage, and apoptosis
Exhibit robust anti-proliferative activity, and result in fragmented nuclei and malformed mitotic spindles in chromosomally instable ovarian cancer cell lines
Induce cell cycle arrest in G2/M for sensitive cell lines, consistent with the role of KIF18A in facilitating mitosis
Lead to dose-dependent tumor growth inhibition in an OVCAR-3 cancer cell line-derived xenograft model, while sparing tumors that are insensitive to KIF18A loss
Data describing a DHX9-specific pharmacodynamic biomarker of inhibition are presented in a poster entitled "circBRIP1 RNA as a non-invasive target engagement pharmacodynamic biomarker for DHX9 inhibition." Key takeaways include:
Positive correlation of circBRIP1 induction with DHX9 biochemical activity, dose, and exposure for DHX9 inhibitors
Similar potency of dose-dependent induction of circBRIP1 across cell lines that are sensitive or insensitive to DHX9 inhibition, indicating that circBRIP1 is a unique target engagement PD biomarker, but not a predictor of DHX9 sensitivity
circBRIP1 induction correlates with DHX9 inhibitor concentration within individual tumors in mouse xenografts, providing strong evidence of a predictable PK/PD relationship
Select posters and presentations will be shared on Accent’s website following the meeting.
About DHX9
Accent’s lead program is a first-in-class DHX9 inhibitor with the potential to address high unmet need indications not adequately served by existing therapies, including tumors with BRCA loss of function (breast, ovarian, and others), mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) cancers (colorectal, endometrial, gastric) and additional undisclosed cancer types representing large patient populations. DHX9 is a DNA/RNA helicase that has been reported to play important roles in replication, transcription, translation, RNA splicing, RNA processing, and maintenance of genomic stability. Hence, this enzyme represents a compelling novel oncology target as inhibition of DHX9 exploits key tumor vulnerabilities, resulting in cancer-specific death. Accent is currently conducting IND-enabling studies for this program.
About KIF18A
Accent’s second lead program is a potential best-in-class inhibitor for KIF18A which may address a large patient population across several cancer indications, including ovarian and triple negative breast cancer (TNBC). KIF18A is a mitotic kinesin motor protein critical for cell division in select tumors with chromosomal instability. A subset of tumor cells with an abnormal number of chromosomes (aneuploid) are reliant on KIF18A and show rapid cell killing in vitro and in vivo upon KIF18A inhibitor treatment, while cells with normal numbers of chromosomes (euploid) are unaffected. Accent is planning to initiate IND-enabling studies for KIF18A in the first half of 2024.