PARP inhibitor "new partner" - CSF-1R inhibitor

Inhibition of PARP is not too toxic to healthy cells because there are multiple signaling paths to repair DNA, but for some tumor cells, these tumor cells are particularly sensitive to PARP inhibitors because specific genetic mutations such as BRCA can disrupt other DNA repair pathfages, which is why ovarian and breast cancer patients with BRCA mutations are more likely to benefit from PARP inhibitors.
, however, a problem that cannot be ignored is that although BRCA-related HER2-negative metastases have a better response rate to PARP inhibitors than standard chemotherapy, and patients have no progression in improving survival, the benefits are short-lived.
response to PARP inhibitors is not long-lasting, and some patients who initially respond to PARP inhibitors often develop resistance.
to solve this problem, some scientists have tried to use PARP inhibitors in combination with immunotherapy.
based on some preclinical data, scientists from Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) speculate that this combined treatment recruits and activates T-cells, which induce the killing of tumor cells.
, however, the results of clinical trials show that the combination therapy strategy of "PARP inhibitors plus immunotherapy" is well-lerated, but not as effective as the single-drug treatment of PARP inhibitors.
DF/BWCC scientists have conducted further research into exactly what caused the results.
: Nature Cancer, in a new study published in the journal Nature Cancer on December 14, revealed that macrophage-mediated immunosuppression is the "main culprit" for the poor efficacy of this combined treatment.
"Why didn't PARP inhibitors plus immunotherapy succeed?" It's very curious.
our new study suggests that some other things in the tumor micro environment, possibly macrophages, limit the activation of T cells.
found that macrophages became highly immunosuppressive after treatment with PARP inhibitors.
, " said Dr. Jennifer Guerriero, who led the study.
macrophages are heterogeneic cell groups, which can be divided into M2-like tumor-promoting estypes and M1-like anti-tumor espressopes.
's extensive indication of macrophages in mouse tumors suggests that M2-like macrophages (tumor-related macrophages) enhance tumor cell proliferation, angiogenes generation and diffusion by secreting cytokines and growth factors, thereby promoting tumor occurrence and metastasis.
study, Dr. Guerriero's team found that after treatment with PARP inhibitors, a large number of macrophages in cancerous tissue expressed a receptor necessary for survival, CSF-1R (colony-active factor 1 receptor).
the tumor state with CSF-1R-positive macrophages (highly immunosuppressive macrophage subtypes).
, they hypothesically, targeting CSF-1R-positive macrophages in combined with PARP inhibitors may induce a stronger anti-tumor response.
Using the BRCA defect three-negative breast cancer mouse model, the team found that the combined use of PARP inhibitors with CSF-1R inhibitors significantly enhanced congenital and adaptive anti-tumor immunity, produced a significant anti-tumor response, and the combined treatment extended the median total survival of mice by 100 days.
In BRCA1 defective triple-negative breast cancer, anti-CSF-1R therapy enhances the efficacy of PARP inhibitors (Source: Nature Cancer) Through multi-histological analysis, studies have further found that PARP inhibitors enhance tumor-promoting characteristics of macrophages by inducing pathogenescation driven by SREBP1 (sterol regulatory element-binding protein 1, a key lipid metabolic regulator).
PARP inhibitors regulate the metabolic ideotypes of differentiated macrophages (Source: Nature Cancer) In the mouse model of invasive triple-negative breast cancer, the triple therapy of "PARP inhibitors plus CSF-1R inhibitors and SREBP1 inhibitors" was able to completely eliminate tumors.
SREBP1 inhibitors "saved" the PD-L1 and CSF-1R expressions induced by PARP inhibitors.
the results suggest that the use of PARP inhibitors directly affects the degree of immunosuppression of macrophages in tumor microencology, according to the researchers.
macrophage-mediated immunosuppression is a disadvantage of PARP inhibitor therapy, and the combination of PARP inhibitors and macrophage-targeting therapy can induce long-term reprogramming of tumor microenvironment, providing a promising treatment strategy for triple negative breast cancer.
as written in the discussion section of the paper: these findings provide a theoretical basis for combining CSF-1R antibodies with PARP inhibitors.
reference: 1 s breast cancer study reveals how macrophages may contribute to a weak spot (Source: Dana-Farber Cancer Institute) 2 s Anita K. Mehta et al. Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nature Cancer (2020).