The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium

Epithelial morphogenesis and stability are essential for normal development and organ homeostasis. The mouse neural plate is a cuboidal epithelium that remodels into a columnar pseudostratified epithelium over the course of 24 hr. Here we show that the transition to a columnar epithelium fails in mutant embryos that lack the tumor suppressor PTEN, although proliferation, patterning and apical-basal polarity markers are normal in the mutants. The Pten phenotype is mimicked by constitutive activation of P13 kinase and is rescued by the removal of PDK1 (PDPK1), but does not depend on the downstream kinases AKT and mTORC1. High resolution imaging shows that PTEN is required for stabilization of planar cell packing in the neural plate and for the formation of stable apical-basal microtubule arrays. The data suggest that appropriate levels of membrane-associated PDPK1 are required for stabilization of apical junctions, which promotes cell elongation, during epithelial morphogenesis

Therapeutic benefit of selective inhibition of p110α PI3-kinase in pancreatic neuroendocrine tumors

Purpose: mutations in the PI3K pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacologic intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance tomTOR-targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown. Experimental Design: in the current study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110 alpha-selective (GDC-0326) inhibitors and isoform-specific PI3K kinase-dead-mutant mice. Results: human and mouse PanNETs showed enhanced pAKT, pPRAS40, and pS6 positivity compared with normal tissue. Although treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110 alpha PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node metastasis compared with vehicle-treated mice. We also demonstrated that tumor and stromal cells are implicated in the antitumor activity of GDC-0326 in RIP1-Tag2 tumors. Conclusions: our data provide a rationale for p110a-selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis

Treatment of cancer with oral drugs: a position statement by the Spanish Society of Medical Oncology (SEOM)

Cancer treatment involves the participation of multiple medical specialties and, as our knowledge of the disease increases, this fact becomes even more apparent. The degree of multidisciplinarity is determined by several factors, which include the severity and type of disease, the increasing diversity in the available pharmacological and non-pharmacological therapies, and the range of specialists involved in cancer therapy, such as medical oncologists, radiotherapists, gynecologists, gastroenterologists, urologists, surgeons, and pneumologists, among others. Across Europe, the situation of cancer care can be variable due to the diversity of health systems, differences in drug reimbursement, and the degree of establishment of Medical Oncology as a medical specialty in the European Union states

Phosphatidylinositol 3-Kinase -Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study

PurposeWe report the first-in-human phase Ia study to our knowledge (ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase (PI3K)-selective inhibitor.Patients and MethodsIn the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily.ResultsOne hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes ( 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%).ConclusionAlpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3K inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors

18F-FDG PET/CT for early prediction of response to neoadjuvant lapatinib, trastuzumab, and their combination in HER2-positive breast cancer: results from Neo-ALTTO

Molecular imaging receives increased attention for selecting patients who will benefit from targeted anticancer therapies. Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) enrolled 455 women with invasive human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared rates of pathologic complete response (pCR) to neoadjuvant lapatinib, trastuzumab, and their combination. Each anti-HER2 therapy was given alone for 6 wk, followed by 12 wk of the same therapy plus weekly paclitaxel. The early metabolic effects of the anti-HER2 therapies on the primary tumors and their predictive values for pCR were assessed in a subset of patients. Methods: eighty-six patients underwent (18)F-FDG PET/CT at baseline and weeks 2 and 6 of anti-HER2 treatment. An imaging core laboratory provided central validation, and 2 independent reviewers, masked to assigned treatment arm and clinical outcomes, performed consensus (18)F-FDG PET/CT readings. Maximum standardized uptake value (SUVmax) reductions from baseline were used to measure metabolic response. Results: seventy-seven of the 86 enrolled patients presented an evaluable baseline (18)F-FDG PET/CT scan; of these, 68 and 66 were evaluable at weeks 2 and 6, respectively. Metabolic responses in the primary tumors were evident after 2 wk of targeted therapy and correlated highly with metabolic responses at week 6 (R(2) = 0.81). pCRs were associated with greater SUVmax reductions at both time points. Mean SUVmax reductions for pCR and non-pCR, respectively, were 54.3% versus 32.8% at week 2 (P = 0.02) and 61.5% versus 34.1% at week 6 (P = 0.02). (18)F-FDG PET/CT metabolic response rates at weeks 2 and 6 were 71.6% and 60%, respectively using European Organization for Research and Treatment of Cancer criteria; pCR rates were twice as high for (18)F-FDG PET/CT responders than nonresponders (week 2: 42% vs. 21%, P = 0.12; week 6: 44% vs. 19%, P = 0.05). Conclusion: early metabolic assessment using (18)F-FDG PET/CT can identify patients with an increased likelihood of pCR after neoadjuvant trastuzumab, lapatinib, or their combination when given with chemotherapy

The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium

Epithelial morphogenesis and stability are essential for normal development and organ homeostasis. The mouse neural plate is a cuboidal epithelium that remodels into a columnar pseudostratified epithelium over the course of 24 hr. Here we show that the transition to a columnar epithelium fails in mutant embryos that lack the tumor suppressor PTEN, although proliferation, patterning and apical-basal polarity markers are normal in the mutants. The Pten phenotype is mimicked by constitutive activation of P13 kinase and is rescued by the removal of PDK1 (PDPK1), but does not depend on the downstream kinases AKT and mTORC1. High resolution imaging shows that PTEN is required for stabilization of planar cell packing in the neural plate and for the formation of stable apical-basal microtubule arrays. The data suggest that appropriate levels of membrane-associated PDPK1 are required for stabilization of apical junctions, which promotes cell elongation, during epithelial morphogenesis

18F-FDG PET/CT for early prediction of response to neoadjuvant lapatinib, trastuzumab, and their combination in HER2-positive breast cancer: results from Neo-ALTTO

Molecular imaging receives increased attention for selecting patients who will benefit from targeted anticancer therapies. Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) enrolled 455 women with invasive human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared rates of pathologic complete response (pCR) to neoadjuvant lapatinib, trastuzumab, and their combination. Each anti-HER2 therapy was given alone for 6 wk, followed by 12 wk of the same therapy plus weekly paclitaxel. The early metabolic effects of the anti-HER2 therapies on the primary tumors and their predictive values for pCR were assessed in a subset of patients. Methods: eighty-six patients underwent (18)F-FDG PET/CT at baseline and weeks 2 and 6 of anti-HER2 treatment. An imaging core laboratory provided central validation, and 2 independent reviewers, masked to assigned treatment arm and clinical outcomes, performed consensus (18)F-FDG PET/CT readings. Maximum standardized uptake value (SUVmax) reductions from baseline were used to measure metabolic response. Results: seventy-seven of the 86 enrolled patients presented an evaluable baseline (18)F-FDG PET/CT scan; of these, 68 and 66 were evaluable at weeks 2 and 6, respectively. Metabolic responses in the primary tumors were evident after 2 wk of targeted therapy and correlated highly with metabolic responses at week 6 (R(2) = 0.81). pCRs were associated with greater SUVmax reductions at both time points. Mean SUVmax reductions for pCR and non-pCR, respectively, were 54.3% versus 32.8% at week 2 (P = 0.02) and 61.5% versus 34.1% at week 6 (P = 0.02). (18)F-FDG PET/CT metabolic response rates at weeks 2 and 6 were 71.6% and 60%, respectively using European Organization for Research and Treatment of Cancer criteria; pCR rates were twice as high for (18)F-FDG PET/CT responders than nonresponders (week 2: 42% vs. 21%, P = 0.12; week 6: 44% vs. 19%, P = 0.05). Conclusion: early metabolic assessment using (18)F-FDG PET/CT can identify patients with an increased likelihood of pCR after neoadjuvant trastuzumab, lapatinib, or their combination when given with chemotherapy

Stratification and therapeutic potential of PML in metastatic breast cancer

Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification