Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma

Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy (BRAF and MEK inhibitors) and immune checkpoint blockade (anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with long-term responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed

High Fiber Dietary Intervention Induces Change in Role of Faecalibacterium Prausnitzii in Gut Microbiome Ecosystem

https://openworks.mdanderson.org/sumexp23/1036/thumbnail.jp

The role of different microbiota in metastatic brain tumors

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Network Analysis of Gut Microbiome Throughout a Whole Foods Based High Fiber Dietary Intervention Reveals Complex Community Dynamics in Melanoma Survivors

https://openworks.mdanderson.org/sumexp22/1139/thumbnail.jp

Impact of a Whole Foods Based High Fiber Diet on Gut Microbiome in Melanoma Survivors

https://openworks.mdanderson.org/sumexp21/1237/thumbnail.jp

Elucidating the Role of Microbiome in Low- and High-Grade Glioma

https://openworks.mdanderson.org/sumexp22/1117/thumbnail.jp

A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. © 2018 AAC

School support, chaos, routines, and parents' mental health during COVID-19 remote schooling

Remote schooling due to Coronavirus Disease 2019 (COVID-19) created profound challenges for families. In this investigation, we examined parents' depression and anxiety during remote schooling and their associations with parents' reports of school support. We also evaluated indirect and interactive (i.e., moderation) associations. Participants were parents (N = 152, 92.8% mothers, 65.1% Black) from an urban area with high rates of COVID-19. Of the 152 parents, 27.6% reported elevated levels of depression and 34.2% reported elevated anxiety. Regression analyses showed that school support was negatively associated with parents' depression (β = -.33, p < .01) and anxiety (β = -.21, p < .01). There was an indirect association between school support and parents' mental health via household chaos and daily routines. Reported COVID-19 impact moderated the direct association between school support and parental depression and anxiety. There was a statistically significant association between school support and parents' depression and anxiety when COVID-19 impact was low or moderate, but not when COVID-19 impact was high. These results may suggest that for parents who were not highly impacted by the pandemic, school support buffered the association between stress and parents' mental health problems; parents most impacted by COVID-19 may need additional support. (PsycInfo Database Record (c) 2022 APA, all rights reserved).K01 MH110600 - NIMH NIH HHS; L40 MH117714 - NIMH NIH HHSAccepted manuscrip

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance

Cancer testis antigen and interleukin expression correlates with survival in small bowel neuroendocrine tumors

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