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IOA-244, a novel p110δ PI3K inhibitor, blocks breast tumour progression on either mono- or combined-therapy
Evangelia Goulielmaki1, Anna Tsapara1, Lydia Xenou1
1Department of Biochemistry, School of Medicine, University of Crete, Heraklion, Greece.
Abstract:
The clinical approval of p110δ PI3K inhibitors raised hopes in treating aggressive tumours expressing high levels of non-mutated p110δ, however, the severe adverse effects that those inhibitors caused became a barrier to their clinical application. IOA-244 is the first-in-class, highly selective and non-ATP competitive p110δ PI3K inhibitor showing high selectivity and low toxicity in several preclinical models. Here we show that IOA-244, as a single agent treatment, blocks the progression of early phase breast tumours by attacking the survival of cancer cells and the polarisation of TAMs to a pro-tumourigenic phenotype leading to suppression of TAMs-expressed ATX. In established tumours, IOA-244 alone was insufficient to control the high levels of both M2-like macrophages and ATX, and while it reduced tumour progression, it did not completely block it. Full tumour control, however, was achieved when IOA-244 used in a combinatorial regimen with the PF-8380 ATX inhibitor. In agreement with the mouse model, the amount of CD163+/CD204+macrophages and ATX were much higher in grade III human breast carcinomas compared to grade I. Our work provides the first in vivo preclinical evidence showing that IOA-244 is a potential highly effective drug for breast cancer treatment and depending on the phase of the tumour can be used either as a single agent or as a combinatorial regimen.
Insights
IOA-244, a novel p110δ PI3K inhibitor, effectively treats early breast tumors by targeting cancer cell survival and tumor-associated macrophages (TAMs). Combination therapy with PF-8380 is needed for advanced tumors.
Area of Science:
- Oncology
- Pharmacology
- Immunology
Background:
- p110δ PI3K inhibitors show promise for aggressive tumors but cause severe adverse effects.
- IOA-244 is a novel, selective, non-ATP competitive p110δ PI3K inhibitor with low toxicity.
- Tumor-associated macrophages (TAMs) and their secreted autotaxin (ATX) play roles in tumor progression.
Purpose of the Study:
- To evaluate the efficacy of IOA-244 as a single agent and in combination with an ATX inhibitor (PF-8380) for breast cancer treatment.
- To investigate the impact of IOA-244 on cancer cell survival and TAM polarization.
- To assess the correlation between macrophage markers, ATX levels, and breast cancer grade.
Main Methods:
- Preclinical breast cancer models (in vivo).
- Treatment with IOA-244 alone and in combination with PF-8380.
- Assessment of tumor progression, cancer cell survival, TAM polarization (M2-like, CD163+/CD204+), and ATX levels.
- Analysis of human breast carcinoma samples (Grade I vs. Grade III).
Main Results:
- IOA-244 as a single agent blocked early-phase breast tumor progression by reducing cancer cell survival and M2-like TAM polarization, suppressing ATX.
- In established tumors, IOA-244 alone partially reduced tumor progression but did not fully control M2-like TAMs and ATX.
- Combination therapy with IOA-244 and PF-8380 achieved complete tumor control in established tumors.
- Higher levels of M2-like macrophages and ATX were observed in Grade III human breast carcinomas compared to Grade I.
Conclusions:
- IOA-244 demonstrates significant preclinical efficacy as a single agent for early breast cancer and in combination for advanced stages.
- The combination of IOA-244 and PF-8380 offers a promising therapeutic strategy for breast cancer by targeting both cancer cells and the tumor microenvironment.
- IOA-244 represents a potential breakthrough in breast cancer treatment due to its selectivity and efficacy across different tumor stages.
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