Dataset Information

Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.

ABSTRACT: The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPK? is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPK? could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPK? or its downstream kinase MK2 each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. This effect was primarily mediated by inhibition of the p38MAPK? pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity that drastically affects quality of life for patients with cancer. These data underscore the vital role played by stromal-derived factors in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss.Significance: Pharmacologically targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth, preserves bone quality, and extends survival. Cancer Res; 78(19); 5618-30. ©2018 AACR.

SUBMITTER: Murali B

PROVIDER: S-EPMC6168362 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.

Murali Bhavna B Ren Qihao Q Luo Xianmin X Faget Douglas V DV Wang Chun C Johnson Radia Marie RM Gruosso Tina T Flanagan Kevin C KC Fu Yujie Y Leahy Kathleen K Alspach Elise E Su Xinming X Ross Michael H MH Burnette Barry B Weilbaecher Katherine N KN Park Morag M Mbalaviele Gabriel G Monahan Joseph B JB Stewart Sheila A SA

Cancer research 20180809 19

The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPKα could reduce breast cancer metastases in a clinically relevant model. Orally administere ...[more]

PMID: 30093561

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Project description:Background:With the occurrence and improvement of immunohistochemistry and other pathological diagnostic techniques, gastrointestinal stromal tumor (GIST) has been gradually recognized. With the prolonged survival of patients with GISTs, reports about the bone metastasis of GIST increased. However, the knowledge of GISTs is rather limited due to its very low incidence. Methods:Cochrane and Medline database (via PubMed) were searched in July 2019 with related keywords to acquire the literature related to the bone metastasis of GIST. Then, the literature was reviewed and references were also scanned to identify the possible related reports. Study data comprising age, sex, primary location, metastasis interval time, immunohistochemistry index, management and prognosis were recorded and analyzed. Results:Forty-five patients with bone metastases of GIST, with a mean age of 61.09 years, were included. The small intestine and stomach were the most common primary sites, followed by the rectum. Patients with small intestine primary sites had bone metastases that occurred earlier than the bone metastases stomach and rectum primary sites. The spine was the most common site of bony metastases. The mean survival time after GIST diagnosis was more than 64.02 months. Patients younger than 60 years old had a worse prognosis than those older than 60 years old. Furthermore, patients with spinal involvement had a worse prognosis than those without spinal involvement. Surgical interventions combined with targeted therapies guaranteed a better prognosis. Conclusion:Bone metastasis of GIST, which mainly occurs in the spine, is rather rare. Patients with GISTs of the small intestine and stomach suffered from bone metastasis more frequently and earlier than patients with GISTs in other primary sites. Age, sex, primary tumor location, treatment mode for the primary lesions and metastases, and spine involvement may be potential factors that affect the prognosis of GIST patients with bone metastases.

Project description:ObjectiveThe study objective was to evaluate the safety, tolerability, pharmacodynamics, and preliminary efficacy of ATI-450 with methotrexate in patients with rheumatoid arthritis (RA).MethodsA parallel-assignment, placebo-controlled, investigator-blinded/patient-blinded multicenter study evaluated patients with moderate-to-severe RA aged 18 to 70 years. Eligible patients were randomized (1:1) to ATI-450 50-mg oral tablets twice daily or placebo with a stable weekly dose of methotrexate for 12 weeks. The primary objective was to assess ATI-450 safety and tolerability. The secondary objectives were to assess the median percentage change from baseline high-sensitivity C-reactive protein (hs-CRP) levels, the mean change from baseline in Disease Activity Score in 28 joints based on CRP level (DAS28-CRP) and Rheumatoid Arthritis Magnetic Resonance Imaging Score hand-wrist assessments of synovitis or bone erosion at week 12, and the proportion of patients with American College of Rheumatology 20/50/70 (ACR 20/50/70) and with DAS28-CRP scores of less than 2.6. The exploratory outcomes were change from baseline in endogenous and ex vivo-stimulated cytokine levels.ResultsATI-450 was well tolerated with no severe adverse events reported. ATI-450 reduced median hs-CRP levels by 42% or more at all posttreatment timepoints. In the ATI-450 group, a mean (median) decrease in DAS28-CRP score of 2.0 (2.1) was observed at week 12; proportions of patients with an ACR 20/50/70 response in the per-protocol population were 60%, 33%, and 20%, respectively, at week 12. Endogenous plasma levels of key inflammatory cytokines (tumor necrosis factor α, macrophage inflammatory protein 1β, interleukin 6, interleukin 8) were reduced across the 12 treatment weeks.ConclusionThis is the first clinical study demonstrating that selective mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) pathway blockade leads to a sustained antiinflammatory effect. This suggests that targeting the MK2 pathway mitigates the tachyphylaxis observed with p38 MAPK inhibitors in RA and supports further exploration.

Dataset Information

Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.

Publications

Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.

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