The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma

Melanoma is known to be a radioresistant cancer. Melanoma radioresistance can be due to several factors such as pigmentation, antioxidant defenses and high Deoxyribonucleic acid (DNA) repair efficacy. However, irradiation induces intracellular translocation of RTKs, including cMet, which regulates response to DNA damage activating proteins and promotes DNA repair. Accordingly, we hypothesized that co-targeting DNA repair (PARP-1) and relevant activated RTKs, c-Met in particular, may radiosensitize wild-type B-Raf Proto-Oncogene, Serine/Threonine Kinase (WTBRAF) melanomas where RTKs are often upregulated. Firstly, we found that PARP-1 is highly expressed in melanoma cell lines. PARP-1 inhibition by Olaparib or its KO mediates melanoma cell sensitivity to radiotherapy (RT). Similarly, specific inhibition of c-Met by Crizotinib or its KO radiosensitizes the melanoma cell lines. Mechanistically, we show that RT causes c-Met nuclear translocation to interact with PARP-1 promoting its activity. This can be reversed by c-Met inhibition. Accordingly, RT associated with the inhibition of both c-Met and PARP-1 resulted in a synergistic effect not only on tumor growth inhibition but also on tumor regrowth control in all animals following the stop of the treatment. We thus show that combining PARP and c-Met inhibition with RT appears a promising therapeutic approach in WTBRAF melanoma

Additive growth inhibitory effects of ibandronate and antiestrogens in estrogen receptor-positive breast cancer cell lines

INTRODUCTION: Bisphosphonates are inhibitors of osteoclast-mediated tumor-stimulated osteolysis, and they have become standard therapy for the management of bone metastases from breast cancer. These drugs can also directly induce growth inhibition and apoptosis of osteotropic cancer cells, including estrogen receptor-positive (ER+) breast cancer cells. METHODS: We examined the anti-proliferative properties of ibandronate on two ER+ breast cancer cell lines (MCF-7 and IBEP-2), and on one ER negative (ER-) cell line (MDA-MB-231). Experiments were performed in steroid-free medium to assess ER regulation and the effect of ibandronate in combination with estrogen or antiestrogens. RESULTS: Ibandronate inhibited cancer cell growth in a dose- and time-dependent manner (approximate IC(50): 10(-4 )M for MCF-7 and IBEP-2 cells; 3 × 10(-4 )M for MDA-MB-231 cells), partly through apoptosis induction. It completely abolished the mitogenic effect induced by 17β-estradiol in ER+ breast cancer cells, but affected neither ER regulation nor estrogen-induced progesterone receptor expression, as documented in MCF-7 cells. Moreover, ibandronate enhanced the growth inhibitory action of partial (4-hydroxytamoxifen) and pure (ICI 182,780, now called fluvestrant or Faslodex™) antiestrogens in estrogen-sensitive breast cancer cells. Combination analysis identified additive interactions between ibandronate and ER antagonists. CONCLUSION: These data constitute the first in vitro evidence for additive effects between ibandronate and antiestrogens, supporting their combined use for the treatment of bone metastases from breast cancer

Immune Cell Density Evaluation Improves the Prognostic Values of Staging and p16 in Oropharyngeal Cancer

The incidence of oropharyngeal cancers (OPSCCs) has continued to rise over the years, mainly due to human papillomavirus (HPV) infection. Although they were newly reclassified in the last TNM staging system, some groups still relapse and have poor prognoses. Based on their implication in oncogenesis, we investigated the density of cytotoxic and regulatory T cells, macrophages, and Langerhans cells in relation to p16 status, staging and survival of patients. Biopsies from 194 OPSCCs were analyzed for HPV by RT-qPCR and for p16 by immunohistochemistry, while CD8, FoxP3, CD68 and CD1a immunolabeling was performed in stromal (ST) and intratumoral (IT) compartments to establish optimal cutoff values for overall survival (OS). High levels of FoxP3 IT and CD1a ST positively correlated with OS and were observed in p16-positive and low-stage patients, respectively. Then, their associations with p16 and TNM were more efficient than the clinical parameters alone in describing patient survival. Using multivariate analyses, we demonstrated that the respective combination of FoxP3 or CD1a with p16 status or staging was an independent prognostic marker improving the outcome of OPSCC patients. These two combinations are significant prognostic signatures that may eventually be included in the staging stratification system to develop personalized treatment approaches

Role of Macrophage Migration Inhibitory Factor (MIF) in Melanoma

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine involved in the carcinogenesis of many cancer types. Here, we review the published experimental and clinical data for MIF and its involvement in melanoma. All reported data show that MIF is overexpressed in melanoma cells, especially in case of metastatic disease. Clinical studies also indicate that high MIF expression is positively associated with aggressiveness of the disease. Some data also highlight the implication of MIF in angiogenesis, immunity and metastasis in melanoma cell lines, as well as the availability of different therapeutic options targeting MIF for the treatment of metastatic melanoma. Indeed, the main problem in metastatic melanoma is the lack of long-term effective treatment. This is linked to the capacity of melanoma cells to mutate very quickly and/or activate alternative signaling pathways. Thus, MIF targeting therapies could provide a new effective way of treating melanoma. Moreover, cell sensitivity to MIF depletion does not correlate with the BRAF mutational status. Regarding the fact that many melanoma patients carry a BRAF mutation, and that they develop resistance to BRAF inhibitors, this observation is very interesting as MIF inhibitors could be used to treat many patients in relapse after treatment with an inhibitor of the mutant BRAF protein

Cytokine Landscape in Central Nervous System Metastases

The central nervous system is the location of metastases in more than 40% of patients with lung cancer, breast cancer and melanoma. These metastases are associated with one of the poorest prognoses in advanced cancer patients, mainly due to the lack of effective treatments. In this review, we explore the involvement of cytokines, including interleukins and chemokines, during the development of brain and leptomeningeal metastases from the epithelial-to-mesenchymal cell transition and blood–brain barrier extravasation to the interaction between cancer cells and cells from the brain microenvironment, including astrocytes and microglia. Furthermore, the role of the gut–brain axis on cytokine release during this process will also be addressed

PRIMA-1 and PRIMA-1Met (APR-246): From Mutant/Wild Type p53 Reactivation to Unexpected Mechanisms Underlying Their Potent Anti-Tumor Effect in Combinatorial Therapies

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Macrophage Profiling in Head and Neck Cancer to Improve Patient Prognosis and Assessment of Cancer Cell–Macrophage Interactions Using Three-Dimensional Coculture Models

Tumor-associated macrophages are key components of the tumor microenvironment and play important roles in the progression of head and neck cancer, leading to the development of effective strategies targeting immune cells in tumors. Our study demonstrated the prognostic potential of a new scoring system (Macroscore) based on the combination of the ratio and the sum of the high and low densities of M1 (CD80+) and M2 (CD163+) macrophages in a series of head and neck cancer patients, including a training population (n = 54) and a validation population (n = 19). Interestingly, the Macroscore outperformed TNM criteria and p16 status, showing a significant association with poor patient prognosis, and demonstrated significant predictive value for overall survival. Additionally, 3D coculture spheroids were established to analyze the crosstalk between cancer cells and monocytes/macrophages. Our data revealed that cancer cells can induce monocyte differentiation into protumoral M2 macrophages, creating an immunosuppressive microenvironment. This coculture also induced the production of immunosuppressive cytokines, such as IL10 and IL8, known to promote M2 polarization. Finally, we validated the ability of the macrophage subpopulations to induce apoptosis (M1) or support proliferation (M2) of cancer cells. Overall, our research highlights the potential of the Macroscore as a valuable prognostic biomarker to enhance the clinical management of patients and underscores the relevance of a spheroid model in gaining a better understanding of the mechanisms underlying cancer cell–macrophage interactions