Inhibition of ribonucleotide reductase subunit M2 enhances the radiosensitivity of metastatic pancreatic neuroendocrine tumor.

Ribonucleotide Reductase (RNR) is a rate-limiting enzyme in the production of deoxyribonucleoside triphosphates (dNTPs), which are essential substrates for DNA repair after radiation damage. We explored the radiosensitization property of RNR and investigated a selective RRM2 inhibitor, 3-AP, as a radiosensitizer in the treatment of metastatic pNETs. We investigated the role of RNR subunit, RRM2, in pancreatic neuroendocrine (pNET) cells and responses to radiation in vitro. We also evaluated the selective RRM2 subunit inhibitor, 3-AP, as a radiosensitizer to treat pNET metastases in vivo. Knockdown of RNR subunits demonstrated that RRM1 and RRM2 subunits, but not p53R3, play significant roles in cell proliferation. RRM2 inhibition activated DDR pathways through phosphorylation of ATM and DNA-PK protein kinases but not ATR. RRM2 inhibition also induced Chk1 and Chk2 phosphorylation, resulting in G1/S phase cell cycle arrest. RRM2 inhibition sensitized pNET cells to radiotherapy and induced apoptosis in vitro. In vivo, we utilized pNET subcutaneous and lung metastasis models to examine the rationale for RNR-targeted therapy and 3-AP as a radiosensitizer in treating pNETs. Combination treatment significantly increased apoptosis of BON (human pNET) xenografts and significantly reduced the burden of lung metastases. Together, our results demonstrate that selective RRM2 inhibition induced radiosensitivity of metastatic pNETs both in vitro and in vivo. Therefore, treatment with the selective RRM2 inhibitor, 3-AP, is a promising radiosensitizer in the therapeutic armamentarium for metastatic pNETs.

Radiotherapy in Managing Metastatic Hepatocellular Carcinoma With Cardiac Involvement and Pulmonary Tumor Thromboemboli: A Case Report.

Hepatocellular carcinoma (HCC) is the most common liver cancer and presents various degrees of aggressiveness. In this case study, we reported the management of an aggressive HCC patient who was a young immigrant from a hepatitis B endemic country with locally advanced HCC with portal involvement at presentation. Patient was initially managed with Yttrium-90 (Y-90) instillation, then systemic treatment when he had disease progression. Despite multiple lines of systemic treatments, patient continued to progress and developed significant cardiac involvement and pulmonary tumor thromboemboli. His course of treatment was further complicated by hemoptysis, presumably from hemorrhagic tumor thromboemboli. Patient became ineligible for systemic treatment due to the risk of hemoptysis, thus, subsequently managed with a course of palliative radiotherapy. Unfortunately, patient developed hemorrhagic shock, cardiac failure, and septic shock during radiation treatment and expired shortly afterward. In this case report, we discussed multi-modal treatments, including Y-90, systemic treatment, and radiotherapy, in managing complicated and aggressive HCC. We also reported risk factors, prognostic factors, efficacy of Y-90 instillation and the necessity of a personalized treatment approach. In conclusion, there is no consensus on managing patients with metastatic HCC with cardiac and pulmonary involvement currently. Treatment modalities are often highly personalized and require multi-disciplinary discussion.

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors.

Patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor overall prognosis despite chemotherapy and radiotherapy (e.g., peptide receptor radionuclide therapy (PRRT)). Better treatment options are needed to improve disease regression and patient survival. The purpose of this study was to examine a new treatment strategy by combining PI3K/mTOR dual inhibition and radiotherapy. First, we assessed the efficacy of two PI3K/mTOR dual inhibitors, PF-04691502 and PKI-402, to inhibit pAkt and increase apoptosis in NET cell lines (BON and QGP-1) and patient-derived tumor spheroids as single agents or combined with radiotherapy (XRT). Treatment with PF-04691502 decreased pAkt (Ser473) expression for up to 72 h compared with the control; in contrast, decreased pAkt expression was noted for less than 24 h with PKI-402. Simultaneous treatment with PF-04691502 and XRT did not induce apoptosis in NET cells; however, the addition of PF-04691502 48 h after XRT significantly increased apoptosis compared to PF-04691502 or XRT treatment alone. Our results demonstrate that schedule-dependent administration of a PI3K/mTOR inhibitor, combined with XRT, can enhance cytotoxicity by promoting the radiosensitivity of NET cells. Moreover, our findings suggest that radiotherapy, in combination with timed PI3K/mTOR inhibition, may be a promising therapeutic regimen for patients with GEP-NET.

Role of AMPK and Akt in triple negative breast cancer lung colonization.

Triple negative breast cancer (TNBC) is an aggressive disease with a 5-y relative survival rate of 11% after distant metastasis. To survive the metastatic cascade, tumor cells remodel their signaling pathways by regulating energy production and upregulating survival pathways. AMP-activated protein kinase (AMPK) and Akt regulate energy homeostasis and survival, however, the individual or synergistic role of AMPK and Akt isoforms during lung colonization by TNBC cells is unknown. The purpose of this study was to establish whether targeting Akt, AMPKα or both Akt and AMPKα isoforms in circulating cancer cells can suppress TNBC lung colonization. Transient silencing of Akt1 or Akt2 dramatically decreased metastatic colonization of lungs by inducing apoptosis or inhibiting invasion, respectively. Importantly, transient pharmacologic inhibition of Akt activity with MK-2206 or AZD5363 inhibitors did not prevent colonization of lung tissue by TNBC cells. Knockdown of AMPKα1, AMPKα2, or AMPKα1/2 also had no effect on metastatic colonization of lungs. Taken together, these findings demonstrate that transient decrease in AMPK isoforms expression alone or in combination with Akt1 in circulating tumor cells does not synergistically reduce TNBC metastatic lung colonization. Our results also provide evidence that Akt1 and Akt2 expression serve as a bottleneck that can challenge colonization of lungs by TNBC cells.

Factors Contributing to Delay in Specialist Care After Colorectal Cancer Diagnosis in Kentucky.

BACKGROUND: Abundant studies have associated colorectal cancer (CRC) treatment delay with advanced diagnosis and worse mortality. Delay in seeking specialist is a contributor to CRC treatment delay. The goal of this study is to investigate contributing factors to 14-d delay from diagnosis of CRC on colonoscopy to the first specialist visit in the state of Kentucky. METHODS: The Kentucky Cancer Registry (KCR) database linked with health administrative claims data was queried to include adult patients diagnosed with stage I-IV CRC from January 2007 to December 2012. The dates of the last colonoscopy and the first specialist visit were identified through the claims. Bivariate and logistic regression analysis was performed to identify factors associated with delay to CRC specialist visit. RESULTS: A total of 3927 patients from 100 hospitals in Kentucky were included. Approximately, 19% of patients with CRC visited a specialist more than 14 d after CRC detection on colonoscopy. Delay to specialist (DTS) was found more likely in patients with Medicaid insurance (OR 3.1, P < 0.0001), low and moderate education level (OR 1.4 and 1.3, respectively, P = 0.0127), and stage I CRC (OR 1.5, P < 0.0001). There was a higher percentage of delay to specialist among Medicaid patients (44.0%) than Medicare (18.0%) and privately insured patients (18.8%). CONCLUSIONS: We identified Medicaid insurance, low education attainment, and early stage CRC diagnosis as independent risk factors associated with 14-d delay in seeking specialist care after CRC detection on colonoscopy.

Targeting PI3K and AMPKα Signaling Alone or in Combination to Enhance Radiosensitivity of Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is characterized by poor survival. Radiotherapy plays an important role in treating TNBC. The purpose of this study was to determine whether inhibiting the AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K) pathways alone or in combination potentiates radiotherapy in TNBC. AMPKα1 and AMPKα2 knockdown diminished cyclin D1 expression and induced G1 cell cycle arrest but did not induce apoptosis alone or in combination with radiotherapy. Next, we analyzed the role of PI3K p85α, p85ß, p110α, p110ß, Akt1, and Akt2 proteins on TNBC cell cycle progression and apoptosis induction. Akt1 and p110α knockdown diminished cyclin D1 expression and induced apoptosis. Silencing Akt1 promoted synergistic apoptosis induction during radiotherapy and further reduced survival after radiation. Treatment with the Akt inhibitor, MK-2206 48 h after radiotherapy decreased Akt1 levels and potentiated radiation-induced apoptosis. Together, our results demonstrate that AMPKα, p110α, and Akt1 promote TNBC proliferation and that Akt1 is a key regulator of radiosensitivity in TNBC. Importantly, combining radiotherapy with the pharmacological inhibition of Akt1 expression is a potentially promising approach for the treatment of TNBC.

Nonadherence to Standard of Care for Locally Advanced Colon Cancer as a Contributory Factor for High Mortality Rates in Kentucky.

BACKGROUND: Kentucky has one of the highest mortality rates for colon cancer, despite dramatic improvements in screening. The National Comprehensive Cancer Network (NCCN) guidelines recommend operation and adjuvant chemotherapy for locally advanced (stage IIb/c and stage III) colon cancer (LACC). The purpose of this study was to determine the rate of nonadherence with current standard of care (SOC) and associated factors as possible contributors to mortality. METHODS: The Kentucky Cancer Registry database linked with administrative health claims was queried for individuals (20 years and older) diagnosed with LACC from 2007 to 2012. Bivariate and logistic regression of nonadherence was performed. Survival analysis was performed with Cox regression and Kaplan-Meier plots. RESULTS: A total of 1,404 patients with LACC were included. Approximately 42% of patients with LACC were noted to be nonadherent to SOC, with nearly all (95.7%) failing to receive adjuvant chemotherapy. After adjusting for all significant factors, we found the factors associated with nonadherence included the following: age older than 75 years, stage III colon cancer, high Charlson Comorbidity Index (3+), low poverty level, Medicaid coverage, and disability. Adherence to SOC is associated with a significant improvement in the 5-year survival rate compared with nonadherence (63.0% and 27.4%, respectively; p < 0.0001). CONCLUSIONS: Our study identified multiple factors associated with the failure of patients with LACC to receive SOC, particularly adjuvant chemotherapy, suggesting the need to focus on improving adjuvant chemotherapy compliance in specific populations. Nonadherence to LACC SOC is likely a major contributor to the persistently high mortality rates in Kentucky.

Evaluation of a Clinical Pharmacist-Led Multidisciplinary Antidepressant Telemonitoring Service in the Primary Care Setting.

Guidelines recommend patient follow-up within 2 weeks of antidepressant initiation or uptitration to minimize treatment discontinuation and suicidal ideation risks; however, time constraints and lack of systematic processes remain barriers in primary care. A pharmacist-led multidisciplinary telemonitoring service aimed to address these barriers. This was a retrospective, observational study of adults with depression initiated or uptitrated on an antidepressant between May and October 2016. Outcomes included the proportion of eligible patients successfully contacted, adherence, adverse effects, suicidal ideations, and pharmacist interventions. Clinical pharmacists successfully reached 258 of 380 (68%) patients and provided follow-up in 298 calls. Patients endorsed antidepressant nonadherence during 56 (19%) calls, adverse effects in 81 (27%) calls, and suicidal ideations in 13 (4%) calls. Pharmacists provided 109 total interventions for 102 patients. The clinical pharmacist-led multidisciplinary antidepressant telemonitoring service is an alternative resource to monitor patients after antidepressant initiation or titration in primary care settings.

A Pharmacist-Physician Collaboration to Optimize Benzodiazepine Use for Anxiety and Sleep Symptom Control in Primary Care.

INTRODUCTION: Benzodiazepines are prescribed inappropriately in up to 40% of outpatients. The purpose of this study is to describe a collaborative team-based care model in which clinical pharmacists work with primary care providers (PCPs) to improve the safe use of benzodiazepines for anxiety and sleep disorders and to assess the preliminary results of the impact of the clinical service on patient outcomes. METHODS: Adult patients were eligible if they received care from the academic primary care clinic, were prescribed a benzodiazepine chronically, and were not pregnant or managed by psychiatry. Outcomes included baseline PCP confidence and knowledge of appropriate benzodiazepine use, patient symptom severity, and medication changes. RESULTS: Twenty-five of 57 PCPs responded to the survey. PCPs reported greater confidence in diagnosing and treating generalized anxiety and panic disorders than sleep disorder and had variable knowledge of appropriate benzodiazepine prescribing. Twenty-nine patients had at least 1 visit. Over 44 total patient visits, 59% resulted in the addition or optimization of a nonbenzodiazepine medication and 46% resulted in the discontinuation or optimization of a benzodiazepine. Generalized anxiety symptom severity scores significantly improved (-2.0; 95% confidence interval (CI): -3.57 to -0.43). CONCLUSION: Collaborative team-based models that include clinical pharmacists in primary care can assist in optimizing high-risk benzodiazepine use. Although these findings suggest improvements in safe medication use and symptoms, additional studies are needed to confirm these preliminary results.