News from AACR 2024: Wednesday’s highlights

San Diego

On the final day of AACR, the plenary session of the Annual Meeting put artificial intelligence at the forefront and featured a stellar lineup of AI and data science experts who discussed AI and topics such as imaging, precision medicine, and drug development.

The closing plenary session ‘Highlights: Vision for the Future’, touched on some of the most important concepts presented during the Annual Meeting. Mikala Egeblad, Bloomberg Distinguished Professor of Tumor Microenvironment, Johns Hopkins University, discussed topics related to basic cancer science and translational research, Melissa Simon, George H Gardner, MD, Professor of Clinical Gynecology, Northwestern Medicine, discussed topics related to prevention, early detection, population sciences, and prevention research, and Ryan Corcoran, Director of the Tucker Gosnell Center for Gastrointestinal Cancers at Massachusetts General Hospital, discussed topics related to clinical research and clinical trials.

It was announced that the next AACR Annual Meeting will take place in Chicago on 25-30 April 2025.

The Program Committee Chairs commented: “It has been an educational, enlightening, and inspiring week of captivating cancer science and research. As we participate in our closing sessions of the AACR Annual Meeting 2024, let us say what an honour and pleasure it has been to serve as the Program Committee Chairs for this year’s meeting. Thanks to all the Program Committee members for assembling an exceptional scientific programme, and AACR leadership and staff for their hard work in bringing this meeting to life. Thanks, too, to the members of the AACR for their support of this organisation’s meaningful mission to prevent and cure all cancers. And thanks to the city of San Diego for its hospitality.”

Research highlights

Blacksmith Medicines announced preclinical data on its oncology programme targeting flap endonuclease 1 (FEN1). The current lead (BSM-1516) is ~65-fold more potent against FEN1 than its related enzyme Exonuclease 1 (Exo1) in biochemical assays (IC50 of 7nM and 460nM, respectively). FEN1 target engagement in live cells was validated by cellular thermal shift assay (CETSA EC50 of 24 nM). Inhibition of FEN1 led to its increased association with chromatin in S-phase cells and recruitment of PARP1 enzyme. In clonogenic assay, BRCA2-deficient DLD1 cells were ~15-fold more sensitive to FEN1 inhibition than their isogenic BRCA2-wild-type counterparts (EC50 of 350nM and 5µM, respectively), confirming the increased susceptibility of HR deficient cancer cells to FEN1 inhibition. Treatment of BRCA2-deficient but not wild-type DLD1 cells with BSM-1516 resulted in cell cycle arrest accompanied by DNA damage signalling and accumulation of chromatin-bound RPA32, a marker of ssDNA.

Aadi Bioscience presented new non-clinical data that highlight the combinability of nab-sirolimus and its potential for synergy to enhance anti-cancer effects and overcome resistance. Nab-sirolimus enhanced the cytotoxic effects of fulvestrant in HR+ breast cancer cells and PI3Ki in both HR+ and HR- breast cancer cells. The addition of nab-sirolimus to endocrine therapy or PI3K-AKT-mTOR pathway inhibitors may mutually overcome mechanisms of resistance induced by single-agent treatments. The company reported that these data further support the combination of nab-sirolimus with endocrine therapy for hormone-driven cancers, as is currently being investigated in patients with advanced or recurrent endometrioid endometrial cancer in a Phase II study.

OBI Pharma: OBI-992 is a TROP2-targeted antibody-drug conjugate (ADC) that carries a potent topoisomerase I inhibitor payload to kill tumour cells. TROP2 is highly expressed in a variety of solid tumours such as lung, breast, ovarian, and gastric cancer, rendering it an ideal target for cancer therapy. OBI-992 uses a unique hydrophilic, enzyme-cleavable linker that is stable in circulation but releases the cytotoxic payload inside tumour cells. The company reported that OBI-992 demonstrates remarkable antitumor efficacy, improved pharmacokinetic characteristics, and a favourable safety profile in animal models. OBI-992 received US IND clearance in December 2023 and Phase I/II efficacy and safety human studies are planned to commence early Q2 2024.

CDR-Life presented preclinical data demonstrating the promising anti-tumour properties of its peptide major histocompatibility complex (pMHC) T-cell engager (TCE) antibodies. The Kita-Kyushu lung cancer antigen-1 (KK-LC-1/CT83) is a promising target because it is not expressed in normal tissues and is highly prevalent across a broad range of cancers including gastric, lung, breast and cervical cancer. CDR-Life’s data gathered on pMHC TCE antibodies with high specificity towards HLA-A*01 restricted KK-LC-1 epitopes demonstrate the antibodies’ promising anti-tumour activity and specificity for KK-LC-1/HLA-A*01 positive tumours. The data showed no evidence for off-target cytotoxic activity towards KK-LC-1-negative/ HLA-A*01-positive healthy human cells. In vitro studies showed significantly higher TCE-dependent T-cell activation towards cells presenting the target peptide compared to the risk peptides.

Laekna presented two preclinical candidates, LAE119, a novel PARP1 selective inhibitor and trapper, and LAE120, a novel selective USP1 inhibitor. LAE119 is a potent and selective PARP1 inhibitor and PARP1-DNA trapper. LAE119 exhibits extremely long residence time on PARP1 in both biochemical and cellular assays and shows good activity even in tumour cells with low PARP1 protein level. It demonstrates robust anti-tumour effect in BRCA2-/- DLD-1 and MDA-MB-436 Xenograft models and has minimal effects on haematologic parameters.

Diana Spencer, Senior Digital Content Editor, DDW

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