Andrea P. Myers

High Frequency of PIK3R1 and PIK3R2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability

We demonstrate that phosphatidylinositol 3-kinase (PI3K) pathway aberrations occur in >80% of endometrioid endometrial cancers, with coordinate mutations of multiple PI3K pathway members being more common than predicted by chance. PIK3R1 (p85α) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85β), not previously demonstrated to be a cancer gene, is also frequently mutated. The dominant activation event in the PI3K pathway appears to be PTEN protein loss. However, in tumors with retained PTEN protein, PI3K pathway mutations phenocopy PTEN loss, resulting in pathway activation. KRAS mutations are common in endometrioid tumors activating independent events from PI3K pathway aberrations. Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85α dimers bind and stabilize PTEN. Taken together, the PI3K pathway represents a critical driver of endometrial cancer pathogenesis and a novel therapeutic target.

Oncogenic mutations in cervical cancer: genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix.

Cervical cancer is the second leading cause of cancer deaths among women worldwide. The objective of this study was to describe the most common oncogenic mutations in cervical cancers and to explore genomic differences between the 2 most common histologic subtypes: adenocarcinoma and squamous cell carcinoma.

What a Tangled Web We Weave: Emerging Resistance Mechanisms to Inhibition of the Phosphoinositide 3-Kinase Pathway

UNLABELLED The phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently mutated pathways in cancer, and is actively being pursued as a therapeutic target. Despite the importance of the PI3K pathway in cancer, durable responses to PI3K pathway-targeted therapies are uncommon with monotherapy. Several in vitro and xenograft models have elucidated compensatory signaling and genomic changes which may limit the therapeutic effectiveness of PI3K inhibitors in the clinic. Future clinical trials with prospective evaluation of tumor signaling and genomic changes are likely to identify novel resistance mechanisms as well as subsets of patients who may derive maximal benefit from PI3K pathway inhibitors. SIGNIFICANCE There are multiple ongoing clinical trials targeting the PI3K pathway members in several malignancies. This review summarizes the known mechanisms of resistance to targeting the PI3K pathway. Understanding of resistance mechanisms will help to inform more rational clinical trial design to optimize the clinical impact of targeting the PI3K pathway in cancer.

A Genetic Mouse Model of Invasive Endometrial Cancer Driven by Concurrent Loss of Pten and Lkb1 Is Highly Responsive to mTOR Inhibition

Signals from the tumor suppressors PTEN and LKB1 converge on mTOR to negatively regulate its function in cancer cells. Notably, both of these suppressors are attenuated in a significant fraction of human endometrial tumors. In this study, we generated a genetic mouse model of endometrial cancer driven by concomitant loss of these suppressors to gain pathophysiological insight into this disease. Dual loss of Pten and Lkb1 in the endometrial epithelium led to rapid development of advanced endometrioid endometrial tumors with 100% penetrance and short host survival. The tumors displayed dysregulated phosphatidylinositol 3-kinase (PI3K)/Akt and Lkb1/Ampk signaling with hyperactivation of mTOR signaling. Treatment with a dual PI3K/mTOR inhibitor, BEZ235, extended the time before tumor onset and prolonged overall survival. The PI3K inhibitor GDC-0941 used as a single agent reduced the growth rate of primary tumor implants in Pten/Lkb1-deficient mice, and the mTOR inhibitor RAD001 was unexpectedly as effective as BEZ235 in triggering tumor regression. In parallel, we also found that ectopic expression of LKB1 in PTEN/LKB1-deficient human endometrial cancer cells increased their sensitivity to PI3K inhibition. Together, our results demonstrated that Pten/Lkb1-deficient endometrial tumors rely strongly on deregulated mTOR signaling, and they provided evidence that LKB1 status may modulate the response of PTEN-deficient tumors to PI3K or mTOR inhibitors.

New Strategies in Endometrial Cancer: Targeting the PI3K/mTOR Pathway—The Devil Is in the Details

Endometrial cancer is the most common gynecologic malignancy in the developed world and affects approximately 40,000 women in the United States each year. The phosphoinositide 3-kinase (PI3K) signaling pathway regulates key aspects of cancer biology including glucose uptake and metabolism, cellular growth, and survival. Endometrial cancers harbor the highest rates of PI3K pathway alterations reported to date. The PI3K pathway is highly druggable and several classes of agents are in clinical development including rapalogs, pan-PI3K inhibitors, PI3K isoform-specific inhibitors, dual PI3K/mTOR catalytic inhibitors, mTOR-specific catalytic inhibitors, and AKT inhibitors. It has been 10 years since the initiation of the first studies of rapalogs as anticancer agents. There are more than 20 registered clinical trials of PI3K/mTOR inhibitors as single agents or in therapeutic combinations for the treatment of endometrial cancers. What have we learned from the completed studies? What can we expect to learn from ongoing studies? What should we anticipate moving forward? Clin Cancer Res; 19(19); 5264–74. ©2013 AACR.

PTEN loss is a context-dependent outcome determinant in obese and non-obese endometrioid endometrial cancer patients

Endometrial cancer incidence is increasing, due in part to a strong association with obesity. Mutations in the phosphatidylinositol 3‐kinase (PI3K) pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid adenocarcinomas, the most common form of endometrial cancer. We sought to determine the impact of PI3K pathway alterations on progression free survival in a cohort of endometrioid endometrial cancers. Prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss by immunohistochemistry, was explored in the context of patient body mass index. Reverse‐phase protein arrays were utilized to assess protein expression based on PTEN status. Among 187 endometrioid endometrial cancers, there were no statistically significant associations between PFS and PIK3CA, PIK3R1, PTEN mutation or loss. When stratified by body mass index, PTEN loss was associated with improved progression free survival (P < 0.006) in obese (body mass index ≥ 30) patients. PTEN loss resulted in distinct protein changes: Canonical PI3K pathway activation was observed only in the non‐obese population while decreased expression of β‐CATENIN and phosphorylated FOXO3A was observed in obese patients. These data suggest the impact of PTEN loss on tumor biology and clinical outcomes must be interpreted in the context of body mass index, and provide a potential explanation for discrepant reports on the effect of PTEN status and obesity on prognosis in endometrial cancer. This reveals a clinically important interaction between metabolic state and tumor genetics that may unveil the biologic underpinning of obesity‐related cancers and impact ongoing clinical trials with PI3K pathway inhibitors.

Targeting a common collaborator in cancer development.

A small-molecule inhibitor of phosphatidylinositol 3-kinase enhances the cytotoxic effects of the common chemotherapeutic agent doxorubicin in breast and ovarian cancer cell lines. In this issue of Science Translational Medicine, Wallin et al. have identified a subset of breast and ovarian cancer cell lines that show synergistic response to the combination of doxorubicin and GDC-0941, a class IA phosphatidylinositol 3-kinase (PI3K) inhibitor. Here, we discuss the potential implications of these data on the clinical development of PI3K pathway inhibitors as cancer therapeutics.

Clinical investigation of receptor and non-receptor tyrosine kinase inhibitors for the treatment of epithelial ovarian cancer.

Introduction: Epithelial ovarian cancer (EOC) is the second most common gynecologic malignancy and the leading cause of death from gynecologic cancer in the USA. EOC is an exquisitely chemo-sensitive disease with response rates of over 75% in the upfront setting. Despite this, due to high rates of recurrence and development of chemo-resistance, the overall survival of EOC remains about 25%. Thus, there is a great need for new therapeutic approaches to render more durable responses. Based on preclinical and early phase clinical studies, key targeted pathways include targets that drive angiogenesis and chemo-resistance. Receptor tyrosine kinases and non-receptor tyrosine kinases play important roles in these processes and several small molecule tyrosine kinase inhibitors (TKIs) are in clinical development. Areas covered: This review summarizes clinical rationale, mechanisms of action and clinical data for the TKIs under evaluation in the Phase III setting for EOC. Expert opinion: Despite reasonable preclinical activity, small molecule TKIs are unlikely to improve patient survival as single agent therapies in an unselected EOC population. Incorporation of tissue evaluation during ongoing clinical trials is required to identify molecularly defined groups that respond to single agents and direct rational combination strategies based on mechanisms of resistance to improve outcomes in EOC.

Images in cardiovascular medicine. Left atrial-esophageal fistula after pulmonary vein isolation: a cautionary tale.

A 56-year-old man presented with a 3-day history of progressive epigastric burning, dysphagia, and tactile fever. These symptoms started approximately 4 weeks after an uncomplicated pulmonary vein isolation procedure for atrial fibrillation had been performed at an outside facility. At the time of presentation, the patient was found to be febrile, and blood cultures were positive for Streptococcus viridans growth. Appropriate antibiotic therapy was started at that time. Chest x-ray did not reveal any abnormal findings. Because endocarditis was suspected, transthoracic and transesophageal echocardiograms were performed, but no valvular abnormalities were found. Subsequently, he developed right arm and right leg weakness and a naming deficit associated with anomia, acalculia, and agraphia. He was then transferred to our hospital for further evaluation. At the time of transfer, the …A 56-year-old man presented with a 3-day history of progressive epigastric burning, dysphagia, and tactile fever. These symptoms started approximately 4 weeks after an uncomplicated pulmonary vein isolation procedure for atrial fibrillation had been performed at an outside facility. At the time of presentation, the patient was found to be febrile, and blood cultures were positive for Streptococcus viridans growth. Appropriate antibiotic therapy was started at that time. Chest x-ray did not reveal any abnormal findings. Because endocarditis was suspected, transthoracic and transesophageal echocardiograms were performed, but no valvular abnormalities were found. Subsequently, he developed right arm and right leg weakness and a naming deficit associated with anomia, acalculia, and agraphia. He was then transferred to our hospital for further evaluation. At the time of transfer, the …

Left Atrial–Esophageal Fistula After Pulmonary Vein Isolation A Cautionary Tale

A 56-year-old man presented with a 3-day history of progressive epigastric burning, dysphagia, and tactile fever. These symptoms started approximately 4 weeks after an uncomplicated pulmonary vein isolation procedure for atrial fibrillation had been performed at an outside facility. At the time of presentation, the patient was found to be febrile, and blood cultures were positive for Streptococcus viridans growth. Appropriate antibiotic therapy was started at that time. Chest x-ray did not reveal any abnormal findings. Because endocarditis was suspected, transthoracic and transesophageal echocardiograms were performed, but no valvular abnormalities were found. Subsequently, he developed right arm and right leg weakness and a naming deficit associated with anomia, acalculia, and agraphia. He was then transferred to our hospital for further evaluation. At the time of transfer, the …A 56-year-old man presented with a 3-day history of progressive epigastric burning, dysphagia, and tactile fever. These symptoms started approximately 4 weeks after an uncomplicated pulmonary vein isolation procedure for atrial fibrillation had been performed at an outside facility. At the time of presentation, the patient was found to be febrile, and blood cultures were positive for Streptococcus viridans growth. Appropriate antibiotic therapy was started at that time. Chest x-ray did not reveal any abnormal findings. Because endocarditis was suspected, transthoracic and transesophageal echocardiograms were performed, but no valvular abnormalities were found. Subsequently, he developed right arm and right leg weakness and a naming deficit associated with anomia, acalculia, and agraphia. He was then transferred to our hospital for further evaluation. At the time of transfer, the …