isolation-characterization-tumor-initiating-cells-from-sarcoma

Isolation and Characterization of Tumor-initiating Cells from Sarcoma Patient-derived Xenografts

The existence and importance of tumor-initiating cells (TICs) have been supported by increasing evidence during the past decade. These TICs have been ...

Icahn School of Medicine at Mount Sinai

Although tyrosine kinase inhibitors (TKIs) have demonstrated significant efficacy in advanced lung adenocarcinoma (LUAD) patients with pathogenic alterations in EGFR, most patients develop acquired resistance to these agents via mechanisms enabling the sustained activation of the PI3K and MAPK oncogenic pathways downstream of EGFR. The tumor suppressor protein phosphatase 2A (PP2A) acts as a negative regulator of these pathways. We hypothesize that activation of PP2A simultaneously inhibits the PI3K and MAPK pathways and represents a promising therapeutic strategy for the treatment of TKI-resistant LUAD. After establishing the efficacy of small molecule activators of PP2A (SMAPs) in a transgenic EGFRL858R model and TKI-sensitive cell lines, we evaluated their therapeutic potential in vitro and in vivo in TKI-resistant models. PP2A activation resulted in apoptosis, significant tumor growth inhibition, and downregulation of PI3K and MAPK pathways. Combination of SMAPs and TKI afatinib resulted in an enhanced effect on the downregulation of the PI3K pathway via degradation of the PP2A endogenous inhibitor CIP2A. An improved effect on tumor growth inhibition was observed in a TKI-resistant xenograft mouse model treated with a combination of both agents. These collective data support the development of PP2A activators for the treatment of TKI-resistant LUAD.

Direct activation of PP2A for the treatment of tyrosine kinase inhibitor-resistant lung adenocarcinoma.

Prostate cancer (PCa) preferentially metastasizes to bone, leading to complications including severe pain, fractures, spinal cord compression, bone marrow suppression, and a mortality of ∼70%. In spite of recent advances in chemo-, hormonal, and radiation therapies, bone-metastatic, castrate-resistant PCa is incurable. PCa is somewhat unique among the solid tumors in its tendency to produce osteoblastic lesions composed of hypermineralized bone with multiple layers of poorly organized type I collagen fibrils that have reduced mechanical strength. Many of the signaling pathways that control normal bone homeostasis are at play in pathologic PCa bone metastases, including the receptor activator of nuclear factor-B/receptor activator of nuclear factor-B ligand/osteoprotegerin system. A number of PCa-derived soluble factors have been shown to induce the dysfunctional osteoblastic phenotype. However, therapies directed at these osteoblastic-stimulating proteins have yielded disappointing clinical results to date. One of the soluble factors expressed by PCa cells, particularly in bone metastases, is prostatic acid phosphatase (PAP). Human PAP is a prostate epithelium-specific secretory protein that was the first tumor marker ever described. Biologically, PAP exhibits both phosphatase activity and ecto-5'-nucleotidase activity, generating extracellular phosphate and adenosine as the final products. Accumulating evidence indicates that PAP plays a causal role in the osteoblastic phenotype and aberrant bone mineralization seen in bone-metastatic, castrate-resistant PCa. Targeting PAP may represent a therapeutic approach to improve morbidity and mortality from PCa osteoblastic bone metastases.

Mechanisms of Osteoblastic Bone Metastasis in Prostate Cancer: Role of Prostatic Acid Phosphatase.

 Adrenal incidentalomas are increasingly detected with the widespread use of thoracic and abdominal imaging. The most common secretory syndrome in adrenal nodules is autonomous cortisol secretion (ACS). Recent data show that even mild cortisol excess is associated with adverse outcomes. The glucocorticoid receptor antagonist mifepristone has been used in patients with overt Cushing's syndrome and hyperglycemia. The purpose of our study was to determine the effect of mifepristone on metabolic parameters in patients with ACS and concomitant prediabetes or diabetes.  Eight patients with either unilateral or bilateral adrenal nodules with ACS were included in the study. Fasting laboratory tests including glucose and insulin levels to calculate HOMA-IR were performed at baseline and again after either 3 months (3 patients) or 6 months (5 patients) on mifepristone 300mg daily treatment. Patients also completed several validated surveys on mood and quality of life at baseline and follow up.  There were significant reductions in fasting glucose measurements and insulin resistance as measured by HOMA-IR in the 6 of 8 study patients in whom these measurements were available (p-value 0.03).  This pilot study demonstrates that mifepristone treatment of ACS is associated with a significant decrease in fasting glucose and insulin resistance as measured by HOMA-IR scores. Mifepristone treatment of ACS may be considered as a medical option for patients with ACS due to adrenal adenomas with concomitant abnormal glucose parameters in whom surgical removal is not being considered.

Article	Year
Direct activation of PP2A for the treatment of tyrosine kinase inhibitor-resistant lung adenocarcinoma. JCI insight\| PubMed ID: 30830869	2019
Mechanisms of Osteoblastic Bone Metastasis in Prostate Cancer: Role of Prostatic Acid Phosphatase. Journal of the Endocrine Society\| PubMed ID: 30842989	2019
MIFEPRISTONE TREATMENT FOR MILD AUTONOMOUS CORTISOL SECRETION DUE TO ADRENAL ADENOMAS: A PILOT STUDY. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists\| PubMed ID: 31070948	2019

Sudeh Izadmehr

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