Loss of cell cycle control is a common feature of most (if not all) human cancers. Thus, cell cycle genes that are frequently dysregulated in malignant cells, including CDK4 and CDK6, have attracted considerable attention as targets for the development of novel anticancer agents. This approach has culminated with the FDA approval of selective CDK4/6 inhibitors (e.g. palbociclib) for the treatment of hormone receptor (HR)+ breast cancer (BC). The same inhibitors are currently being tested in patients with a variety of solid and hematological tumors, including mantle cell lymphoma (MCL). However, not all BC and MCL patients achieve durable complete responses on CDK4/6 inhibitors, calling for the development of mechanism-based combination therapies. In this context, focal radiation therapy (RT) stands out as a promising therapeutic partner because both RT and CDK4/6 inhibitors have cytostatic/cytotoxic as well as immunostimulatory effects, but they operate with different mechanisms. We therefore decided to investigate the potential synergy/cooperation between RT and CDK4/6 inhibitors, with a particular focus on administration schedule, to inform the design of clinical trials testing the combination of these therapeutic agents in patients with HR+HER2-BC and MCL. We harnessed palbociclib-sensitive and -resistant MCL cells (MAVER-1 and MAVER-1R) and BC cells (MCF7 and MBA-MB-231) to investigate the ability of RT to synergize with palbociclib in vitro. In addition, we tested these combinations in vivo, in a unique immunocompetent mouse model of mammary carcinogenesis that recapitulates multiple immunobiological features of human HR+HER2-BC. In this model endogenous mammary carcinomas are driven by a slow-release progesterone pellet plus DMBA as an oral carcinogen. We first determined the lowest doses of RT and palbociclib that mediate robust short-term cytostatic/cytotoxic effects in BC and MCL cells. Optimized dose combinations and sequencing experiments pointed to RT followed by palbociclib as the approach with superior therapeutic potential, in vitro. This largely reflects the ability of palbociclib to induce G1 arrest of cells that escaped RT killing during G2/M arrest. In addition, low doses of RT were able to enhance palbociclib sensitivity in MAVER-1R cells. Both RT and palbociclib were active in the endogenous mammary carcinomas model, but failed to mediate disease eradication. In vivo experiments showed that RT preceding CDK4/6 inhibition achieved superior disease control, compared to other sequencing regimens. In conclusion, our results identified an optimal therapeutic sequence to combine RT and CDK4/6 inhibition in preclinical models of BC and MCL, providing a rational for combining stereotactic body RT and palbociclib in a clinical trial for patients with newly diagnosed HR+ oligo-metastatic BC (up to five metastatic lesions). Future directions include the evaluation of the immunostimulatory effects of RT plus palbociclib in the same models of BC and MCL. Supported by SU2C-Ziskin's Award # ZP-6177. Citation Format: Giulia Petroni, Maurizio Di Liberto, Aitziber Buqué Martinez, Selina Chen-Kiang, Lorenzo Galluzzi, Silvia C. Formenti. Radiation therapy as a tool to sensitize HR+ breast cancer and mantle cell lymphoma to CDK4/6 inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4840.
Tryptophan (Trp) is an essential amino acid which in mammalian cells 90% is processed through the kynurenine pathway. Kynurenine metabolites are among the most potent regulators of immune responses. Herein we report the characterization of a novel immunosuppressant biogenic amine, 3-hydroxy-L-kynurenamine (3HKA), generated through an uncharacterized lateral pathway of Trp catabolism, involving its decarboxylation by the aromatic amino acid decarboxylase. 3HKA is generated by both professional (Dendritic Cells, DC) and non-professional (Lymphatic Endothelial Cells) APC. Quantitative phosphoproteomic analysis of human-monocytes (CD14 +) derived DCs, identified key signaling transduction receptors, IFNR1, and signaling molecules from the JAK/STAT and cAMP mediated PKA pathways, regulated by 3HKA. Cell-based assays coupled with ELISA platforms showed that 3-HKA inhibited the IFN-g-mediated STAT1/NF-kB pathway in human DCs, and consequent decreased the release of pro-inflammatory chemokines and cytokines IL-1, TNFa, IL-6, and IL12p70. In vivo, 3-HKA reduced the intestinal inflammation in a model of dextran sodium sulfate-induced colitis. Furthermore, flow cytometry analysis revealed that 3-HKA increased the number of T-cells expressing 2, 3 or 4 exhaustion markers (PD-1, CTLA4, LAG3 or TIM3), exclusively in CD8 +CD4 −cells. We used, in silico approaches for ligand and pharmacophore-based drug discovery and developed 30 novel 3-HKA analogues with ADMET predicted drug-like properties. Structure-activity relationships studies, leaded to identify compounds with improved anti-inflammatory profiles. The novel anti-inflammatory 3-HKA analogues showed promising activity for the treatment of autoimmune diseases
Background: Macroautophagy (autophagy) is an evolutionary conserved cellular mechanism culminating with the lysosomal degradation of dispensable, damaged or potentially toxic cytoplasmic structures (e.g., permeabilized mitochondria). Autophagy helps cancer cells to adapt to harsh environmental conditions and to resist therapy. However, autophagy is also key for multiple steps of the anticancer immune response. Thus, whether autophagy should be inhibited or activated in the context of cancer therapy remains debated (Rybstein et al., Nat Cell Biol 2018). Since autophagy has been shown to play a key role in removal of cytosolic DNA, which is one mechanism leading to type I interferon (IFN) secretion, and since type I IFN is required for systemic immune responses activated by radiation therapy (RT), we asked the question as to whether selectively inhibiting autophagy in cancer cells may boost the ability of RT to initiate anticancer immunity. Methods/Tools: CRISPR/Cas9 technology was used to render mouse mammary carcinoma TSA and EO771 cells autophagy-deficient and chemical inhibitors of autophagy were also employed. Autophagy-competent versus –deficient systems were characterized for autophagy proficiency (by immunoblotting), growth (in vitro and in vivo), resistance to cell death induced by starvation, chemotherapy and RT (by multicolor flow cytometry and clonogenic assays) and production of type I IFN (by PCR and ELISA). Abscopal responses have been assessed in vivo. Results: In line with previous observations, autophagy inhibition reduced the growth of mouse mammary carcinoma cells, in vitro and in vivo, limited their clonogenic potential (at baseline) and increased their sensitivity to multiple stressors. Moreover, pharmacologic and genetic autophagy inhibition increased the capacity of mouse mammary carcinoma cells to secrete type I IFN in response to radiation. Finally, immunocompetent mice bearing syngeneic autophagy-deficient mouse mammary carcinoma cells mounted improved abscopal responses to RT (in the context of CTLA4 blockade) as compared to immunocompetent mice bearing syngeneic autophagy-competent cells, as determined by growth inhibition of a distant, non-irradiated, autophagy-competent lesion. Perspectives: We will test the innovative hypothesis that selective autophagy inhibition in cancer cells may synergize with autophagy activation at the whole-body level (by nutrient restriction or physical exercise), hence enabling superior therapeutic responses to radiation. Citation Format: Marissa Rybstein, Takahiro Yamazaki, Aitziber Buque Martinez, Lorenzo Galluzzi. Enhancing abscopal responses to radiation therapy by manipulating autophagy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A150.
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