Anti‐tumor effects of PIM / PI 3K/ mTOR triple kinase inhibitor IBL ‐302 in neuroblastoma

Abstract

The PI 3K pathway is a major driver of cancer progression. However, clinical resistance to PI 3K inhibition is common. IBL ‐302 is a novel highly specific triple PIM , PI 3K, and mTOR inhibitor. Screening IBL ‐302 in over 700 cell lines representing 47 tumor types identified neuroblastoma as a strong candidate for PIM / PI 3K/ mTOR inhibition. IBL ‐302 was more effective than single PI 3K inhibition in vitro, and IBL ‐302 treatment of neuroblastoma patient‐derived xenograft ( PDX ) cells induced apoptosis, differentiated tumor cells, and decreased N‐Myc protein levels. IBL ‐302 further enhanced the effect of the common cytotoxic chemotherapies cisplatin, doxorubicin, and etoposide. Global genome, proteome, and phospho‐proteome analyses identified crucial biological processes, including cell motility and apoptosis, targeted by IBL ‐302 treatment. While IBL ‐302 treatment alone reduced tumor growth in vivo , combination therapy with low‐dose cisplatin inhibited neuroblastoma PDX growth. Complementing conventional chemotherapy treatment with PIM / PI 3K/ mTOR inhibition has the potential to improve clinical outcomes and reduce severe late effects in children with high‐risk neuroblastoma.

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

“…AUM302 and the combination of AZD-1208 + BEZ235 affect a different set of genes and phosphoproteins, despite theoretically targeting the same proteins. AUM302 seems to affect similar genes to AZD-1208, which might suggest it preferentially targets the PIM pathway, despite exhibiting a lower IC50 for PIK3CA 20 . The combination of AZD-1208 + BEZ235, appears to exhibit greater inhibitory effects towards PI3K/mTOR.…”

“…With an IC50 an order of magnitude lower than the AZD-1208 + BEZ235 combination, the multikinase inhibitor could potentially reduce adverse effects and allow for the co-targeting approach to be used clinically. Mohlin et al also reported the IC50 for AUM302 in neuroblastoma models to be in the nanomolar range 20 . Furthermore, adverse effects are a major issue of nontargeted prostate cancer treatments 37 ; the development of new therapeutic strategies that would have less impact on the patients' quality of life could significantly improve the current standard of care.…”

Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer

“…In preclinical studies IBL-202, a dual targeting PIM and PI3K inhibitor, has demonstrated superior cytotoxic activity in CLL cells in vitro compared to PI3K inhibitor Idelalisib alone, in addition to significantly reducing the proliferative, migratory capacity of leukaemia cells (Crassini, 2018). cisplatin inhibited neuroblastoma PDX growth (Mohlin et al, 2019). IBL-302 may also benefit one third of patients with breast cancer who have a mutated PI3K pathway and those with resistant triple negative breast cancer who have high PIM kinase expression (Horiuchi et al, 2016).…”

Hypoxia inducible factor‐2α importance for migration, proliferation, and self‐renewal of trunk neural crest cells

“…We have previously shown that the PI3K pathway regulates HIF-2α specifically via mTORC2 and in addition is a promising treatment strategy using a triple PIM/PI3K/mTOR inhibitor in trunk neural crest-derived tumor form neuroblastoma. 27,28 Thus, this would be an interesting mechanism to investigate further. Given the effects we observed on embryonic development in vivo, we mapped potential upstream regulators of arrest in embryo growth (one of the identified top processes by RNA sequencing data).…”

“…Of note, we have recently identified that PI3K-mTORC2 regulates HIF-2α expression and functions as a valid treatment target in neuroblastoma. 27,28 Genes associated with migration of tumor cells mainly encode for plasma membrane and secreted proteins, including several members of the matrix metalloproteinase (MMP) family. MMPs promote invasion and migration by degrading components of the extracellular matrix and have been shown to be regulated by HIF-2α in several different tumor forms, 37,38 further reinforcing a possible connection between HIF-2α, trunk neural crest cells and invasive migratory behavior.…”