Characterization and targeting of phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in renal cell cancer.

BACKGROUND: PI3K and mTOR are key components of signal transduction pathways critical for cell survival. Numerous PI3K inhibitors have entered clinical trials, while mTOR is the target of approved drugs for metastatic renal cell carcinoma (RCC). We characterized expression of p85 and p110α PI3K subunits and mTOR in RCC specimens and assessed pharmacologic co-targeting of these molecules in vitro. METHODS: We employed tissue microarrays containing 330 nephrectomy cases using a novel immunofluorescence-based method of Automated Quantitative Analysis (AQUA) of in situ protein expression. In RCC cell lines we assessed synergism between PI3K and mTOR inhibitors and activity of NVP-BEZ235, which co-targets PI3K and mTOR. RESULTS: p85 expression was associated with high stage and grade (P < 0.0001 for both). High p85 and high mTOR expression were strongly associated with decreased survival, and high p85 was independently prognostic on multi-variable analysis. Strong co-expression of both PI3K subunits and mTOR was found in the human specimens. The PI3K inhibitor LY294002 and rapamycin were highly synergistic in all six RCC cell lines studied. Similar synergism was seen with all rapamycin concentrations used. NVP-BEZ235 inhibited RCC cell growth in vitro with IC(50)s in the low ηM range and resultant PARP cleavage. CONCLUSIONS: High PI3K and mTOR expression in RCC defines populations with decreased survival, suggesting that they are good drug targets in RCC. These targets tend to be co-expressed, and co-targeting these molecules is synergistic. NVP-BEZ235 is active in RCC cells in vitro; suggesting that concurrent PI3K and mTOR targeting in RCC warrants further investigation.

Targeting angiogenesis in bladder cancer.

In most cases, death from bladder cancer results from metastatic disease. Understanding the closely linked mechanisms of invasion, metastasis, and angiogenesis in bladder cancer has allowed development of new therapeutic strategies that may lead to improvements in patient survival. Vascular endothelial growth factor levels appear to be prognostic for outcomes in advanced bladder cancer, and preclinical evaluation of angiogenesis inhibition demonstrates anticancer activity. Antiangiogenic agents such as sunitinib, sorafenib, and bevacizumab are being tested in advanced bladder cancer. This review highlights the key developments in antiangiogenic therapy as it relates to bladder cancer treatment.

Development and Application of a Machine Learning Approach to Assess Short-term Mortality Risk Among Patients With Cancer Starting Chemotherapy.

Importance: Patients with cancer who die soon after starting chemotherapy incur costs of treatment without the benefits. Accurately predicting mortality risk before administering chemotherapy is important, but few patient data-driven tools exist. Objective: To create and validate a machine learning model that predicts mortality in a general oncology cohort starting new chemotherapy, using only data available before the first day of treatment. Design, Setting, and Participants: This retrospective cohort study of patients at a large academic cancer center from January 1, 2004, through December 31, 2014, determined date of death by linkage to Social Security data. The model was derived using data from 2004 through 2011, and performance was measured on nonoverlapping data from 2012 through 2014. The analysis was conducted from June 1 through August 1, 2017. Participants included 26 946 patients starting 51 774 new chemotherapy regimens. Main Outcomes and Measures: Thirty-day mortality from the first day of a new chemotherapy regimen. Secondary outcomes included model discrimination by predicted mortality risk decile among patients receiving palliative chemotherapy, and 180-day mortality from the first day of a new chemotherapy regimen. Results: Among the 26 946 patients included in the analysis, mean age was 58.7 years (95% CI, 58.5-58.9 years); 61.1% were female (95% CI, 60.4%-61.9%); and 86.9% were white (95% CI, 86.4%-87.4%). Thirty-day mortality from chemotherapy start was 2.1% (95% CI, 1.9%-2.4%). Among the 9114 patients in the validation set, the most common primary cancers were breast (21.1%; 95% CI, 20.2%-21.9%), colorectal (19.3%; 95% CI, 18.5%-20.2%), and lung (18.0%; 95% CI, 17.2%-18.8%). Model predictions were accurate for all patients (area under the curve [AUC], 0.940; 95% CI, 0.930-0.951). Predictions for patients starting palliative chemotherapy (46.6% of regimens; 95% CI, 45.8%-47.3%), for whom prognosis is particularly important, remained highly accurate (AUC, 0.924; 95% CI, 0.910-0.939). To illustrate model discrimination, patients were ranked initiating palliative chemotherapy by model-predicted mortality risk, and observed mortality was calculated by risk decile. Thirty-day mortality in the highest-risk decile was 22.6% (95% CI, 19.6%-25.6%); in the lowest-risk decile, no patients died. Predictions remained accurate across all primary cancers, stages, and chemotherapies, even for clinical trial regimens that first appeared in years after the model was trained (AUC, 0.942; 95% CI, 0.882-1.000). The same model also performed well for prediction of 180-day mortality (AUC for all patients, 0.870 [95% CI, 0.862-0.877]; highest- vs lowest-risk decile mortality, 74.8% [95% CI, 72.7%-77.0%] vs 0.2% [95% CI, 0.01%-0.4%]). Predictions were more accurate than estimates from randomized clinical trials of individual chemotherapies or the Surveillance, Epidemiology, and End Results data set. Conclusions and Relevance: A machine learning algorithm using electronic health record data accurately predicted short-term mortality among patients starting chemotherapy. Further research is necessary to determine the generalizability and feasibility of applying this algorithm in clinical settings.

Applied Informatics Decision Support Tool for Mortality Predictions in Patients With Cancer.

PURPOSE: With rapidly evolving treatment options in cancer, the complexity in the clinical decision-making process for oncologists represents a growing challenge magnified by oncologists' disposition of intuition-based assessment of treatment risks and overall mortality. Given the unmet need for accurate prognostication with meaningful clinical rationale, we developed a highly interpretable prediction tool to identify patients with high mortality risk before the start of treatment regimens. METHODS: We obtained electronic health record data between 2004 and 2014 from a large national cancer center and extracted 401 predictors, including demographics, diagnosis, gene mutations, treatment history, comorbidities, resource utilization, vital signs, and laboratory test results. We built an actionable tool using novel developments in modern machine learning to predict 60-, 90- and 180-day mortality from the start of an anticancer regimen. The model was validated in unseen data against benchmark models. RESULTS: We identified 23,983 patients who initiated 46,646 anticancer treatment lines, with a median survival of 514 days. Our proposed prediction models achieved significantly higher estimation quality in unseen data (area under the curve, 0.83 to 0.86) compared with benchmark models. We identified key predictors of mortality, such as change in weight and albumin levels. The results are presented in an interactive and interpretable tool ( www.oncomortality.com ). CONCLUSION: Our fully transparent prediction model was able to distinguish with high precision between highest- and lowest-risk patients. Given the rich data available in electronic health records and advances in machine learning methods, this tool can have significant implications for value-based shared decision making at the point of care and personalized goals-of-care management to catalyze practice reforms.

Accreditation Standard Guideline Initiative for Tai Chi and Qigong Instructors and Training Institutions.

Evidence of the health and wellbeing benefits of Tai Chi and Qigong (TQ) have emerged in the past two decades, but TQ is underutilized in modern health care in Western countries due to lack of promotion and the availability of professionally qualified TQ instructors. To date, there are no government regulations for TQ instructors or for training institutions in China and Western countries, even though TQ is considered to be a part of Traditional Chinese medicine that has the potential to manage many chronic diseases. Based on an integrative health care approach, the accreditation standard guideline initiative for TQ instructors and training institutions was developed in collaboration with health professionals, integrative medicine academics, Tai Chi and Qigong master instructors and consumers including public safety officers from several countries, such as Australia, Canada, China, Germany, Italy, Korea, Sweden and USA. In this paper, the rationale for organizing the Medical Tai Chi and Qigong Association (MTQA) is discussed and the accreditation standard guideline for TQ instructors and training institutions developed by the committee members of MTQA is presented. The MTQA acknowledges that the proposed guidelines are broad, so that the diversity of TQ instructors and training institutions can be integrated with recognition that these guidelines can be developed with further refinement. Additionally, these guidelines face challenges in understanding the complexity of TQ associated with different principles, philosophies and schools of thought. Nonetheless, these guidelines represent a necessary first step as primary resource to serve and guide health care professionals and consumers, as well as the TQ community.

Assessment and management of advanced adrenocortical carcinoma using a precision oncology care model.

Within the category of orphan diseases and rare malignancies, adrenocortical carcinoma (ACC) represents an aggressive entity with high mortality and morbidity. While localized tumors which are diagnosed early can be cured with surgical intervention, there are prognostic factors which predict for micrometastases and consequent recurrent and advanced disease. In such cases, cytotoxic chemotherapy and mitotane have been utilized with a very modest degree of benefit. The poor prognosis of recurrent and advanced ACC has underscored the interest in nuanced characterization of ACC cases using next-generation sequencing (NGS)-based genomic and other '-omic' profiling to guide the precision medicine approach and personalized use of targeted and novel therapies.

Duration of Androgen Deprivation Therapy for High-Risk Prostate Cancer: Application of Randomized Trial Data in a Tertiary Referral Cancer Center.

INTRODUCTION: We evaluated the incidence and predictors of the use of long-term (2-3 years) versus shorter term androgen deprivation therapy (ADT) in radiation-managed men with high-risk prostate cancer. PATIENTS AND METHODS: We identified 302 patients from the Dana-Farber Cancer Institute patient registry who had been diagnosed with high-risk prostate cancer (T3a or prostate-specific antigen [PSA] > 20 ng/mL or Gleason score 8-10) from 1993 to 2015. We assessed the intended duration of ADT and used multivariable Cox regression to evaluate the predictors of receiving a shorter course of ADT than recommended by the guidelines (< 2 years). RESULTS: The course of ADT intended by physicians increased after the 2008/2009 publication of trials showing the superiority of long-term versus short-term ADT, with 43.5% intending ≥ 2 years before versus 61.4% after (P = .014). Starting in 2010, 49.4% of patients actually received < 2 years of ADT. The most common reasons for receipt of shorter course ADT were intolerance of ADT side effects, patient comorbidity/age, the presence of T3a on magnetic resonance imaging only as the sole high-risk feature, or participation in a clinical trial. Moderate to severe comorbidity assessed using the Adult Comorbidity Evaluation-27 (adjusted hazard ratio [AHR] = 2.94), Gleason score < 8 (AHR = 5.66), and PSA < 20 ng/mL (AHR = 4.19) all predicted for receipt of shorter course ADT (P < .05 for all). CONCLUSION: In a tertiary-care setting, the rates of long-course ADT for high-risk disease have increased since the 2008/2009 trials supporting its use. However, approximately one half of patients continued to receive shorter course ADT, often because of intolerance of side effects, underlying comorbidity, or physician judgment about the aggressiveness of the disease.

A phase I study of everolimus and docetaxel in patients with castration-resistant prostate cancer.

BACKGROUND: The PTEN tumor suppressor is frequently lost in CRPC, with activation of Akt-mTOR signaling, driving growth. We conducted a phase I trial of the mTOR inhibitor, everolimus, and docetaxel in CRPC. PATIENTS AND METHODS: Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Patients received everolimus 10 mg daily for 2 weeks and underwent a restaging FDG-PET/computed tomography scan. Patient cohorts were subsequently treated at 3 dose levels of everolimus with docetaxel: 5 mg to 60 mg/m(2), 10 mg to 60 mg/m(2), and 10 mg to 70 mg/m(2). The primary end point was the safety and tolerability of combination therapy. RESULTS: Accrual was 4 patients at level 1, 3 patients at level 2, and 8 patients at level 3. Common toxicities were hematologic and fatigue. Serum concentrations of everolimus when administered with docetaxel were 1.5 to 14.8 ng/mL in patients receiving 5 mg everolimus and 4.5 to 55.4 ng/mL in patients receiving 10 mg everolimus. Four patients had partial metabolic response (PMR) using FDG-PET, 12 had stable metabolic disease, and 2 had progressive metabolic disease after a 2-week treatment with everolimus alone. Five of 12 evaluable patients experienced a prostate-specific antigen (PSA) reduction ≥ 50% during treatment with everolimus together with docetaxel. All 4 patients with a PMR according to PET imaging experienced a PSA reduction in response to everolimus with docetaxel, and 3 of 4 had PSA declines ≥ 50%. CONCLUSION: Everolimus 10 mg daily and docetaxel 60 mg/m(2) was safe in CRPC patients and these were the recommended doses in combination. FDG-PET response might serve as a biomarker for target inhibition by mTOR inhibitors.

Racial disparities in an aging population: the relationship between age and race in the management of African American men with high-risk prostate cancer.

PURPOSE: To evaluate the relationship between age and race on the receipt of definitive therapy among men with high-risk prostate cancer (CaP). METHODS: We used the Surveillance, Epidemiology and End Results Program to identify 62,644 men with high-risk CaP (PSA >20 or Gleason 8-10 or stage ≥cT3a) diagnosed from 2004 to 2010. Multivariable logistic regression analysis modeled the interaction between age and race and its association with receipt of definitive therapy on 57,674 patients (47,879 white men; 9,795 African American [AA] men) with complete data on the covariates of interest. RESULTS: Among men age ≥70, AA men had a higher risk of CaP-specific mortality (PCSM) compared to white men after adjusting for sociodemographic and prostate cancer-specific factors (Adjusted HR 1.20; 95% CI 1.02-1.38; P=0.02). Nevertheless, a significant interaction between race and age was found (Pinteraction=0.01), such that the adjusted odds of receiving definitive treatment for AA vs. white was 0.67 (95% CI 0.62-0.73; P<0.001) among men age <70, but was 0.60 (95% CI 0.55-0.66; P<0.001) among men age ≥70, suggesting increased racial disparity in the receipt of definitive treatment among older men. CONCLUSION: AA men with high-risk CaP are less likely to receive definitive therapy than white men. This disparity is significantly larger among men age ≥70, despite excess PCSM among AA men in this group. With a rapidly expanding population of older minority men, this disparity should be urgently addressed to prevent increasing disparities in cancer care.

Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.

Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or "personalized") medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.

The PI3 kinase signaling pathway in prostate cancer.

Despite recent advances in our understanding of the biological basis of prostate cancer, the management of the disease, especially in the castration-resistant phase, remains a significant challenge. Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is increasingly implicated in a number of malignancies, including prostate carcinogenesis. In this review, we detail the role of this pathway in the pathogenesis of prostate cancer and the therapeutic implications of targeting it.

Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial.

PURPOSE: Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. PATIENTS AND METHODS: Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment. RESULTS: One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%). CONCLUSION: Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

Novel molecular targets for the therapy of renal cell carcinoma.

Emerging from a largely cytokine-based era, the last several years have witnessed a dramatic change in the therapeutic landscape of renal cancer. Molecularly targeted and antiangiogenic agents now form the backbone of most therapeutic strategies for patients with metastatic renal cell carcinoma (mRCC). Although the next few years may not see such broad paradigm shifts, there are ongoing areas of development including vaccine and immunotherapies which do diverge from this paradigm and hold promise to improve therapeutic outcomes for patients with mRCC.

Predictors of response to sequential sunitinib and the impact of prior VEGF-targeted drug washout in patients with metastatic clear-cell renal cell carcinoma.

OBJECTIVE: To identify factors that can be used to identify metastatic clear cell RCC patients more likely to benefit from sequential sunitinib. PATIENTS AND METHODS: We identified patients who failed sorafenib or bevacizumab and subsequently received sunitinib. We looked at objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) to sunitinib in relation to baseline clinical variables. RESULTS: Seventy-one patients received sunitinib sequential therapy. Median duration of follow-up after starting sunitinib was 9.3 months. Median PFS was 5.8 months; median OS was not reached. Significantly higher ORR was seen in patients with normal hemoglobin (25.6%) [defined as >12 gm/dl for female; >13 gm/dl for male]. In addition, a shorter PFS for patients with low hemoglobin, and patients with time from diagnosis to first treatment ≤ 1 year was found. There was a shorter OS for patients ≥ 60 years old, with brain metastasis, low hemoglobin, and time from diagnosis to treatment ≤ 1 year. There was no difference in ORR, PFS, or OS in patients who started sunitinib after or within a 30-day period. CONCLUSIONS: Metastatic clear-cell RCC patients with anemia have less clinical benefit from sequential sunitinib after failure of bevacizumab or sorafenib. Other factors associated with poor outcome include brain metastases, older age, and <1 year between diagnosis and first treatment. Importantly, no difference in outcomes was observed if sequential therapy was initiated within or after 30 days. External validation and prospective evaluation are needed to confirm these findings.

Novel agents for advanced bladder cancer.

Conventional front-line platinum-based combination chemotherapy yields high response rates but suboptimal long-term outcomes for advanced transitional cell carcinoma. Salvage therapy is an unmet need with disappointing outcomes. The emergence of novel biologic agents offers the promise of improved outcomes. Neoadjuvant therapy preceding cystectomy for muscle-invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biologic agents are reviewed.

The developing trend of monoclonal antibodies in the treatment of colorectal cancer.

Monoclonal antibodies (mAbs) against growth factors, receptors and tumor-specific/tumor-selective antigens represent a rapidly growing class of pharmaceutical agents which are poised to make a major impact on the treatment of colorectal cancer. mAbs targeting the epidermal growth factor receptor and the vascular endothelial growth factor have already been approved for the treatment of metastatic colorectal cancer. Other antibodies to the same and other molecular targets implicated in tumor growth and metastasis are undergoing intense preclinical and clinical evaluation. In both the neoadjuvant and adjuvant clinical settings, although mAbs are typically administered in combination with established cytotoxic chemotherapy regimens given their synergistic effect, several agents have demonstrated efficacy when given as monotherapy. At the same time, combination therapies with multiple targeted biological agents are actively being investigated. Existing clinical data and recent progress in preclinical and clinical studies of mAbs are reviewed.