LP-284 showed superior antitumor activity compared with LP-184 independent of PTGR1 expression levels in DNA damage repair–deficient mantle cell lymphoma cell lines.
LP-284 showed superior antitumor activity compared with LP-184 independent of PTGR1 expression levels in DNA damage repair (DDR)–deficient mantle cell lymphoma cell (MCL) lines, according to findings from a preclinical study that were presented at the 2022 SOHO Annual Meeting.1
“LP-284 is a promising preclinical DNA damaging agent that targets DDR deficient cells. LP-284 possesses nanomolar-range anti-tumor activities in multiple and diverse MCL cell lines, with the potential to treat MCL patients who are resistant to other therapies,” the study authors wrote in the poster.
MCL is a rare and aggressive form of B-cell non-Hodgkin lymphoma (NHL). Between 40% and 50% of patients with MCL harbor inactivating mutations in the gene ATM, which plays a key role in the cell’s DNA damage response system. MCL cells with mutations in ATM have increased chromosomal imbalance, copy number loss, and hypersensitivity to DNA damaging agents.
LP-184 is a small molecule DNA damaging agent that has synthetic lethality in DDR-deficient tumors. However, DNA damage by LP-184 is dependent on activation by the oxidoreductase prostaglandin reductase 1 (PTGR1), which is expressed at low levels in many hematological cancers.
LP-284 is an enantiomer of LP-184 that retains synthetic lethality in cancers with impaired DNA damage repair pathway genes, with activity independent of PTGR1 expression.
In preclinical models, LP-284 demonstrated in vitro and in vivo antitumor activity across a range of non-Hodgkin B-cell lymphomas.2 Of the lymphomas tested to date, LP-284 demonstrated the most efficacy in MCL cell lines, including those that are resistant to ibrutinib (Imbruvica) and bortezomib (Velcade).
As part of the study, investigators evaluated whether PTGR1 is needed to activate LP-284, whether LP-284 is a synthetically lethal drug targeting DDR deficiency, and the tumoricidal activity of LP-284 in NHL cell lines.
Within the first part of the study, investigators treated wild-type and PTGR1 CRISPRi Capan-1 and Panc03.27 pancreatic cell lines with LP-284. The IC50 of the Capan-1 and Panc03.27 wild-type cell lines were 441 and 554 nM vs 327 and 646 nM in the PTGR1 and Panc03.27 -/- cell lines, respectively, indicating that PTGR1 expression level does not affect the LP-284 IC50 in these cell lines. “LP-284 is not dependent on PTGR1 for activity and potency,” the authors wrote.
Additionally, in a heatmap representing the IC50 sensitivity of LP-184 and LP-284 across NCI60 tumor cell lines, LP-284 demonstrated increased sensitivity to hematological cancers compared with LP-184.
Subsequently, CHO cells were treated with LP-284. CHO cells carrying nucleotide-excision repair (NER) mutations were up to approximately 4 times more sensitive to LP-284 than their parent wild-type cells.
Investigators also evaluated the effect of the 5 most common gene mutations in MCL on treatment with LP-284 in vitro; these included ATM (42%), CCND1 (22%), TP53 (20%), MLL2 (13%), and MLL3 (11%).
Isogenic cell lines GM00637 and GM05849, which were proficient and deficient in ATM respectively, were treated with LP-284 to determine their IC50 sensitivity. Notably, GM05849 cells, which are ATM deficient, were approximately 1.5 times more sensitive to LP-284 compared with GM00637 cells that were ATM proficient.
Finally, investigators evaluated the IC50s of NHL cell lines treated with LP-284. All 6 of the MCL cell lines, including MINO, MAVER1, JEKO1, JVM2, Z138, and REC1, had some of the lowest IC50s tested, which included drug resistant cell lines. The aforementioned cell lines had documented drug resistance to bortezomib; ibrutinib and venetoclax (Venclexta); zanubrutinib (Brukinsa); unknown; ibrutinib; and bortezomib, respectively, with IC50s to LP-284 of 88, 193, 263, 343, 370, and 794 nM, respectively.
Lantern is planning to submit an Investigational New Drug application for LP-284 in the first quarter of 2023 and anticipates launching a phase 1 clinical trial in the second quarter of 2023.2