LP-284 Shows Preclinical Activity in ATM-Mutated MCL

The investigational agent LP-284 demonstrated activity in multiple mantle cell lymphoma (MCL) cell lines, according to preclinical research presented in a poster at the 2022 Society of Hematologic Oncology annual meeting.¹

LP-284, a small molecule next-generation acylfulvene developed by Lantern Pharma, was found to have antitumor activity across non-Hodgkin lymphomas (NHL) when tested on in vitro and in vivo models, with MCL cell lines showing greater sensitivity to the drug. Its mechanism of action makes it effective in cancers with impaired DNA damage repair (DDR) pathway genes that are expressed in MCL, and it showed activity even in cells that were resistant to approved therapies for MCL.

Since inactivating mutations in the ATM (ataxia telangiectasia mutated) gene associated with DNA repair occur frequently in MCL, the disease is more likely to be hypersensitive to DNA damaging agents. Another agent from Lantern Pharma with the same mechanism of action, LP-184, has shown preclinical activity in other cancer types including pancreatic cancer and glioblastoma, but its activity is dependent on expression of PTGR1 (oxidoreductase prostaglandin reductase 1) which is not frequently expressed in MCL and other hematologic malignancies.

Investigators synthesized LP-284 as an enantiomer of LP-184 that would not depend on PTGR1 expression. When tested on 2 pancreatic cancer cell lines, LP-284 showed similar half maximal inhibitory concentration (IC50) potency, whether the cell lines were PTGR1 wild-type or mutated. When applied to NCI60 solid tumor and hematologic cancer cell lines, LP-284 had significantly better IC50 responses in hematologic tumor cell lines compared with LP-184.

The agent’s efficacy in DDR–deficient cells was investigated in CHO (Chinese hamster ovary) cell lines, showing that those with nucleotide-excision repair mutations were up to approximately 4 times more sensitive to LP-284 than wild-type parent cells.

Two isogenic cell lines were treated with LP-284: GM00637, which is proficient in ATM, and GM05849, which is deficient in this gene. The GM05849 cells were approximately 1.5 times more sensitive to treatment versus GM00637 based on relative cell survival percentage, suggesting that LP-284 is lethal to ATM-deficient tumor cells.

When tested in NHL cell lines including MCL, double-hit, double-expressor, Burkitt, and anaplastic large cell lymphomas, all 6 MCL cell lines tested had among the lowest IC50 sensitivity levels, suggesting LP-284 has greater potency in MCL. These MCL cell lines were known to be resistant to drugs such as bortezomib (Velcade), ibrutinib (Imbruvica), venetoclax (Venclexta), and zanubrutinib (Brukinsa). The lowest IC50 sensitivity value of 88 nM was found in the MINO MCL cell line, which was resistant to bortezomib, followed by the MAVER1 MCL cell line with an IC50 sensitivity value of 193 nM, which was resistant to ibrutinib and venetoclax.

Based on these data, LP-284 has potential to have antitumor activity in patients with MCL with an ATM mutation or other DDR deficiency whose disease is resistant to other therapies. Lantern Pharma stated in a press release that they intend to make an Investigational New Drug submission for LP-284 in the first quarter of 2023 and anticipates launching a phase 1 clinical trial in the second quarter of 2023 in patients with MCL.²

_References:

_{1. Zhou J, Sturtevant D, Biyani N, Bhatia K, Dave S. LP-284 - a highly potent small molecule targeting mantle cell lymphoma. Poster presented at: The Tenth Annual Meeting of the Society of Hematologic Oncology; September 28-October 1, 2022; Houston, TX. Accessed November 17, 2022. https://bit.ly/3XnEmI7}

_{2. Lantern Pharma to present positive preclinical data on the efficacy of LP-284 for mantle cell lymphoma at the Society of Hematologic Oncology Annual Meeting. Lantern Pharma. September 23, 2022. Accessed November 17, 2022. https://bit.ly/3UNutBu}