IOA-244(p110δ PI3K) Stops Breast Tumor Progression Mono/Combo Tx

The experimental compound IOA-244 is targeted to the p110δ isoform of phosphoinositide 3‑kinase (PI3K) and is active in preclinical models of several cancers including breast cancer. Initial data suggest that IOA-244 may be effective in inhibiting progression of early stage cancer and potentially act synergistically with compounds targeting the tumor microenvironment to control advanced disease.

Detailed Insights Into IOA-244

IOA-244 is a first-in-class, non-ATP competitive p110δ PI3K inhibitor with severe adverse effect risk. It is expected to be highly selective and low toxic, based on preclinical data. IOA-244 targets both cancer cells and the supportive Tumor MicroEnvironment (TME).

Why It Matters

PI3K enzymes function as cellular molecular switches governing a variety of cellular biological functions including proliferation and survival as well as immune responses. Small molecule inhibitors of the p110δ isoform of PI3K have been developed as cancer therapeutics since p110δ represents a key molecular switch that controls growth and survival pathways utilized in cancer. However, available p110δ inhibitors have severe, life threatening immune-related side effects which have precluded clinical development and raised serious concerns regarding their use in cancer patients.

Novel Differences

In early clinical trials in patients with AML, IOA-244 appears to be active and is expected to be introduced for clinical testing in the near future. Initial laboratory and clinical data suggest that it may lack some of the immune damaging properties associated with prior PI3Kdelta antagonists, while retaining broad targeting of crucial tumor survival pathways. In preclinical studies, the compound preserved anti-tumor T-cell responses and showed anti-tumor activity in models of multiple cancer types. While this alone is no guarantee of clinical success, it means there will be a safer PI3Kdelta blocker available that could possibly reopen the door to patients with many different cancer types for whom prior PI3Kdelta antagonists were too toxic.

IOA-244 is active against cancer cells and induces a change in the tumour microenvironment from pro-tumorigenic to anti-tumorigenic. Importantly, IOA-244 ablates the pro-migration and pro-survival function of tumour-associated macrophages. Although IOA-244 induces sensitivity of early tumours composed of a majority of highly dividing cells to single agent treatment, established tumours with complex tumour biology may be treated with IOA-244 as part of rational combinations. Of relevance, ATX inhibitors have emerged as promising anti-cancer agents that block cell migration and survival. IOA-244 is an attractive partner for combination treatment with ATX inhibitors. For early-stage disease, IOA-244 can be used as a single agent, for more aggressive or established disease, it can be added to effective combinations.

what the data says

The efficacy of the combination IOA-244 is dependent on the timing and the degree of maturation of the tumor micro-environment.