Targeting Cellular Metabolism With CPI-613 Sensitizes Pancreatic Cancer Cells to Radiation Therapy

PURPOSE: Local tumor progression is a cause of significant morbidity and mortality in patients with pancreatic ductal adenocarcinoma (PDAC) with surgically unresectable disease. Novel and effective approaches to accomplish durable local control are urgently needed. We tested whether CPI-613 (devimistat), a first-in-class investigational small molecule inhibitor of mitochondrial metabolism, was capable of altering cancer cell energy metabolism and sensitizing PDAC cells to radiation therapy (RT). METHODS AND MATERIALS: The effect of a combined treatment of RT with CPI-613 on the viability of, clonogenic potential of, and cell death induction in PDAC cells (MiaPaCa-2 and Panc-1) was determined using a trypan blue dye exclusion assay, a colony formation assay, and a 7-amino-actinomycin D assay, respectively. The synergistic effects of CPI-613-RT and chemotherapeutic agents (gemcitabine or 5-fluorouracil) were measured in MiaPaCa-2 cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and spheroid formation assay. Changes in energy metabolism were determined by profiling metabolites treated with either RT, CPI-613, or both using liquid chromatography-mass spectrometry. RESULTS: This study demonstrates that a combination of single-fraction RT (2 and 10 Gy) with CPI-613 significantly inhibits PDAC cell growth compared with RT alone. Molecular analysis revealed inhibition of α-ketoglutarate dehydrogenase at the protein level. In addition, we demonstrate enhanced cell death of PDAC cells when treated with RT-CPI-613 combination. Targeted metabolomic analysis on PDAC cells post-CPI-613-RT treatment revealed alterations in key mitochondrial metabolites, with broader target engagement by the combination treatment, indicating the sensitization of CPI-613-treated PDAC cells to RT. Furthermore, a combination treatment of CPI-613 with either gemcitabine or 5-fluorouracil in the presence of 2 Gy RT synergistically inhibits PDAC cell proliferation. CONCLUSIONS: Our results support a novel combination of CPI-613-RT that warrants further preclinical and early-phase clinical investigations. A phase 1 trial designed to identify the maximum tolerated dose of CPI-613 in combination with chemo-RT in patients with PDAC was recently initiated (NCT05325281)

A phase I study of CPI-613 (devimistat) in combination with chemoradiation in patients with pancreatic adenocarcinoma

Background: Local tumor progression is a cause of significant mortality and morbidity in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). Effective approaches to achieve durable local control are urgently needed. Metabolic reprogramming and enhanced mitochondrial function, both hallmarks of PDAC, are known contributors to chemo- and radio-resistance. CPI-613, a lipoic acid analog that selectively inhibits components of the Krebs cycle in tumors, showed promising preclinical synergy in combination with gemcitabine and radiation therapy (gem-RT). Methods: We describe a single-arm, single-center, open-label, phase I study designed to determine the maximumtolerated dose of CPI-613 when used concomitantly with gemcitabine and intensity modulated radiation therapy (IMRT) for local control of PDAC. CPI-613 will be administered once weekly by intravenous infusion over approximately 2 hours at a starting dose of 500 mg/m2 and dose-escalated/de-escalated using a Bayesian optimal interval design. Gemcitabine will be given once weekly at 400 mg/m2 dosage and IMRT as 54 Gray (Gy) in 30 fractions (1.8 Gy per fraction) with five fractions given per week. Up to 24 patients will be enrolled for the study after meeting the following main eligibility criteria, which include: pathologically confirmed PDAC; inoperable disease that by institutional pancreatic multidisciplinary tumor board or multidisciplinary review are considered to benefit from definitive local control of the primary tumor; ECOG of 0-2; and adequate organ and marrow function after completion of intended systemic chemotherapy. The secondary objectives are to determine the recommended phase II dose of CPI-613 when used with gem-RT, safety and tolerability of CPI-613-gem-RT, overall survival, local progression-free survival (PFS), overall PFS, patient-reported quality of life after treatment, and late gastrointestinal toxicities following treatment with CPI-613-gem-RT

Third national surveillance of risk factors of non-communicable diseases (SuRFNCD-2007) in Iran: methods and results on prevalence of diabetes, hypertension, obesity, central obesity, and dyslipidemia

<p>Abstract</p> <p>Background</p> <p>The burden of non-communicable diseases is rising globally. This trend seems to be faster in developing countries of the Middle East. In this study, we presented the latest prevalence rates of a number of important non-communicable diseases and their risk factors in the Iranian population.</p> <p>Methods</p> <p>The results of this study are extracted from the third national Surveillance of Risk Factors of Non-Communicable Diseases (SuRFNCD-2007), conducted in 2007. A total of 5,287 Iranian citizens, aged 15–64 years, were included in this survey. Interviewer-administered questionnaires were applied to collect the data of participants including the demographics, diet, physical activity, smoking, history of hypertension, and history of diabetes. Anthropometric characteristics were measured and serum biochemistry profiles were determined on venous blood samples. Diabetes (fasting plasma glucose ≥ 126 mg/dl), hypertension (systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or use of anti-hypertensive drugs), dyslipidemia (hypertriglyceridemia: triglycerides ≥ 150 mg/dl, hypercholesterolemia: total cholesterol ≥ 200 mg/dl), obesity (body mass index ≥ 30 kg/m²), and central obesity (waist circumference ≥ 80 cm in females and ≥ 94 cm in males) were identified and the national prevalence rates were estimated.</p> <p>Results</p> <p>The prevalence of diabetes, hypertension, obesity, and central obesity was 8.7% (95%CI = 7.4–10.2%), 26.6% (95%CI = 24.4–28.9%), 22.3% (95%CI = 20.2–24.5%), and 53.6% (95%CI = 50.4–56.8%), respectively. The prevalence of hypertriglyceridemia and hypercholesterolemia was 36.4% (95%CI = 34.1–38.9%) and 42.9% (95%CI = 40.4–45.4%), respectively. All of the mentioned prevalence rates were higher among females (except hypertriglyceridemia) and urban residents.</p> <p>Conclusion</p> <p>We documented a strikingly high prevalence of a number of chronic non-communicable diseases and their risk factors among Iranian adults. Urgent preventive interventions should be implemented to combat the growing public health problems in Iran.</p

Systemic Therapy of Metastatic Pancreatic Adenocarcinoma: Current Status, Challenges, and Opportunities

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by nonspecific presenting symptoms, lack of a screening test, rapidly progressive clinical course, and presentation with an advanced-stage disease in the majority of patients. PDAC is essentially a systemic disease irrespective of the initial stage, as most patients with non-metastatic PDAC undergoing curative-intent treatment eventually experience metastatic relapse. Currently, cytotoxic chemotherapy remains the cornerstone of treatment in patients with advanced disease. However, the current standard treatment with multiagent chemotherapy has modest efficacy and results in median overall survival (OS) of less than a year and a 5-year OS of about 10%. The pathobiology of PDAC poses many challenges, including a unique tumor microenvironment interfering with drug delivery, intratumoral heterogeneity, and a strongly immunosuppressive microenvironment that supports cancer growth. Recent research is exploring a wide range of novel therapeutic targets, including genomic alterations, tumor microenvironment, and tumor metabolism. The rapid evolution of tumor genome sequencing technologies paves the way for personalized, targeted therapies. The present review summarizes the current chemotherapeutic treatment paradigm of advanced PDAC and discusses the evolving novel targets that are being investigated in a myriad of clinical trials

Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm

Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC

Zero-mismatch deceased-donor kidney versus simultaneous pancreas-kidney transplantation.

BackgroundPatients with type 1 diabetes mellitus (T1DM) and end-stage renal disease may receive a simultaneous pancreas-kidney (SPK), living-donor kidney (LDK), or deceased-donor kidney (DDK) with possible pancreas after kidney transplantation. SPK is associated with superior patient and kidney graft survival compared with DDK, whereas SPK and LDK have comparable outcomes. It is unclear whether SPK and LDK offer a survival benefit over zero-mismatch (0MM) DDK. In this study, we compared the outcomes of T1DM recipients using data from the Organ Procurement and Transplant Network/United Network for Organ Sharing.MethodsAdult (≥18 years) first-time transplant recipients with T1DM waitlisted for SPK and transplanted from 1995 to 2010 were included in this study. Patient and death-censored kidney graft survival were compared between 0MMDDK (n=228), mismatched (MM) DDK (n=964), 0MMSPK (n=215), MMSPK (n=11951), 2 haplotype identical (2hap) LDK (n=205), and non-2hapLDK (n=1719) recipients. Multivariate analysis was performed using stepwise Cox proportional hazards models.ResultsAt 7 years, patient and death-censored graft survival of 0MMDDK recipients (85% and 81%, respectively) were not statistically different from that of 0MMSPK (81% and 85%; log-rank P value vs. 0MMDDK, 0.17 and 0.48, respectively) and 2hapLDK recipients (89% and 86%; log-rank P value vs. 0MMDDK, 0.34 and 0.18, respectively). Among all groups, MMDDK showed the worst patient survival (71%; log-rank P value vs. 0MMDDK, 0.001)ConclusionPatient and kidney graft survival of 0MMDDK recipients were comparable to both SPK and LDK recipients. These findings suggest that T1DM patients awaiting SPK may consider accepting a 0MMDDK if an offer is available

Kidney failure requiring kidney transplantation after pancreas transplant alone.

Pancreas transplant alone (PTA) is usually performed in type 1 diabetic patients with preserved renal function to correct severe metabolic complications. One of the major concerns is renal failure after PTA. Here, we reported the cumulative incidence of kidney failure requiring kidney transplantation (KF/KT) among PTA recipients in the United States. Using the Organ Procurement Transplant Network/ United Network for Organ Sharing database, all primary adult PTA recipients with estimated baseline glomerular filtration rate (by the Modification of Diet in Renal Disease equation) &gt;or=60 mL/min/1.73m2 were selected (n=1085). KF/ KT after PTA was defined as: wait-listing for or receiving a kidney alone (KA) or simultaneous pancreas kidney (SPK) transplant. The median follow-up time was 1185 days (25-75%: 524-2183). Ten years post PTA, 120 (11.1%) patients developed KF/KT; of those, 70 (6.5%) subsequently received a KA/SPK transplant (56 received KA and 14 received SPK) and 50 (4.6%) recipients were listed without receiving a transplant. The cumulative incidence of KF/KT after PTA at 1, 3, and 5 years after PTA was 0.3, 2.5, and 9.7%, respectively. In conclusion, KF/KT after PTA was not uncommon (9.7% at 5 years), and prospective PTA recipients should be aware of the risks of kidney failure after transplantation

Renal Transplant Outcomes in Waitlist Candidates with a Previous Inactive Status Due to Being Temporarily Too Sick.

BackgroundIn 2003, the United Network for Organ Sharing (UNOS) changed its policy to allow candidates with 'inactive' status to accrue time on the waitlist. In this study, we assessed the transplant outcomes among deceased donor kidney transplant (DDKT) recipients who were temporarily inactive specifically due to medical reason, i.e., being temporarily too sick (reason 7).MethodsUsing the UNOS database, adult DDKT recipients were divided into two groups: those who had never been inactivated (active group) and those with a history of being inactive due to reason 7 (reason 7 group). Patient and graft survival, 3-year risk of death, and graft failure were examined and compared.ResultsAfter 3 years of follow-up, patient survival in the reason 7 group was significantly lower than that of the active group (88.14% versus 91.93%, p &lt; 0.01). The reason 7 group had a 20% increased risk of death (hazard ratio, HR 1.20, confidence interval, CI 1.04 - 1.38), a 16% increase in graft failure (HR 1.16, CI 1.06-1.28), and a 15% decrease in death-censored graft failure (HR 1.15, CI 1.01-1.31).ConclusionRecipients with a history of reason 7 have lower patient and graft survival when compared to the active group. Nonetheless, the margins of difference are minimal. Candidates with a history of reason 7 should not be discouraged from transplantation once they return to active status. Standardized criteria for placing candidates on inactive status should be developed to reduce disparities among transplant centers

PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation