Citations

Abstract Introduction: Renal cell carcinoma (RCC) is the most common malignancy of the kidney, responsible for 13,000 deaths in the United States annually. Patients who present with the clear cell (ccRCC) variant of this disease demonstrate a worse prognosis as compared to other subtypes. Due to its asymptomatic nature, patients often do not demonstrate signs of illness until the disease has progressed to an advanced stage. It is estimated that 30% of patients present with metastatic disease at initial diagnosis, and 20-30% of patients with localized cases treated surgically relapse with metastatic disease likely due to the presence of undetectable micrometastases. The treatment for metastatic disease is limited due to its profound resistance against chemotherapy, radiation, and current FDA approved targeted therapies. Despite advances in treatment strategies for patients with metastatic RCC, there remains a need for identification of tumor-specific therapeutic targets. Additionally, elucidation of key signatures which contribute to the development of metastatic disease is paramount. Our group has identified secreted neuronal pentraxin 2 (NPTX2) as a novel oncogenic factor that is highly overexpressed specifically in ccRCC at all stages of disease, and facilitates tumor cell invasion through its interaction with the ionotropic glutamate receptor 4 subunit (GluR4). Methods: NPTX2 expression was evaluated by Affymetrix gene array and immunohistochemistry analysis of patient tumor tissue compared to matched normal samples. Nextbio meta-analysis was used to evaluate NPTX2 expression patterns among RCC subtypes and disease staging. Lentiviral mediated knock-down of NPTX2 and GluR4 was performed in representative ccRCC cell lines and resulting changes in proliferation, viability, morphology, and invasion were evaluated. NPTX2-GluR4 interactions were evaluated via immunoprecipitation, immunofluorescence, and intracellular calcium assays. Results: NPTX2 mRNA and protein is consistently elevated in the clear cell variant of RCC at all stages of disease, and is important for tumor cell viability. We correlate NPTX2 expression with an invasive phenotype, and demonstrate that over-expression of NPTX2 in tumor cells leads to actin cytoskeletal remodeling and increased invasion. We identify GluR4 as a mediator for NPTX2 activity which leads to increased intracellular calcium influx in tumor cells. Conclusions: NPTX2 is a tumor-specific factor that is consistently over-expressed in ccRCC. We further identify GluR4 as a downstream mediator of NPTX2 activity, whereby it modulates intracellular calcium levels, actin cytoskeletal remodeling, and tumor cell invasion. Inhibition of NPTX2 or GluR4 expression via shRNA leads to decreased tumor cell proliferation and invasion, and induces programed cell death. We propose NPTX2 as a new candidate for targeted therapy not previously described in cancer, whose inhibition may demonstrate a clinical benefit in patients suffering from metastatic ccRCC. Citation Format: Christina A. von Roemeling, Derek C. Radisky, Laura A. Marlow, Simon J. Cooper, Stefan K. Grebe, Panagiotis Z. Anastasiadis, Han W. Tun, John A. Copland. Neuronal Pentraxin 2: a novel tumor-specific molecular target that mediates clear cell renal cell carcinoma malignancy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-111. doi:10.1158/1538-7445.AM2014-LB-111

Abstract Background: I-SPY 2 is a multicenter, phase II neoadjuvant trial in women with high-risk stage II/III breast cancer using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard chemotherapy. Primary endpoint is pathologic complete response (pCR). Goal is to identify regimens that meet a high Bayesian predictive probability of statistical significance in a neoadjuvant 300-patient phase III trial defined by hormone-receptor (HR), HER2 status, and MammaPrint (MP). Experimental regimens may “graduate” in 1 of 10 signatures, with a maximum of 120 patients. We report efficacy results for neratinib (N). Methods: Tumors ≥2.5cm by clinical exam & ≥2cm by imaging are eligible for screening. MP low risk/HR+/HER2- tumors are ineligible for randomization. Patients receive chemotherapy (paclitaxel qwk x 12, doxorubicin and cyclophosphamide q2-3 wk x 4, T->AC). HER2- pts were randomized to N+T->AC vs. T->AC and HER2+ pts to N+T->AC vs. trastuzumab+T->AC. Analysis is intent-to-treat with pts who switch to non-protocol therapy regarded as non-pCRs. We provide estimated pCR rates (95% Bayesian probability intervals), probabilities of superiority of neratinib over control, and Bayesian predictive probabilities of success in an equally randomized phase III trial. Results: Neratinib met the predictive probability criterion in HR-/HER2+, “graduated”, and accrual ceased [115 N patients (65 HER2+), 78 concurrently randomized controls (22 HER2+)]. The table shows results for all 10 signatures. Two patients (1 N and 1 control) withdrew consent and are not included. Conclusion: I-SPY 2's standing trial mechanism efficiently evaluates agents in biomarker-defined patient subsets. In a modest number of patients, adaptive randomization successfully identified a biomarker signature (HR-/HER2+) for neratinib's further development. All HER2+ and MP+ tumors may also benefit from this regimen, consistent with preclinical data. Evaluation in I-SPY 3, a phase III registration trial, is planned. SignatureEstimated pCR Rate (95% probability interval)Probability NeratinibIs Superior to ControlPredictive Probability of Success in Phase IIINeratinibControlALL32% (28-36%)23% (19%-28%)92%44%HR+23% (18%-28%)17% (11%-22%)81%40%HR-43% (37%-49%)31% (24%-38%)89%53%HER2+39% (33%-45%)23% (15%-30%)95%73%HER2-26% (21%-32%)24% (18%-29%)63%20%MP+*45% (38%-53%)29% (20%-39%)91%66%HR-/HER2-36% (29%-43%)30% (23%-38%)72%34%HR-/HER2+55% (46%-64%)32% (22%-43%)94%78%HR+/HER2+31% (24%-37%)17% (10%-24%)91%65%HR+/HER2-14% (8%-19%)16% (10%-21%)39%12%* MammaPrint 44K Array Low/High score was adjusted to MammaPrint High1 (MP-) or High2 (MP+), using a pre-defined median cut-point of I-SPY 1 participants, who fit the eligibility criteria of I-SPY 2. Citation Format: John W. Park, Minetta C. Liu, Douglas Yee, Angela DeMichele, Laura van 't Veer, Nola Hylton, Fraser Symmans, Meredith B. Buxton, A. Jo Chien, Amy Wallace, Michelle Melisko, Richard Schwab, Judy Boughey, Debashish Tripathy, Hank Kaplan, Rita Nanda, Stephen Chui, Kathy S. Albain, Stacy Moulder, Anthony Elias, Julie E. Lang, Kirsten Edminston, Donald Northfelt, David Euhus, Qamar Khan, Julia Lyandres, Sarah E. Davis, Christina Yau, Ashish Sanil, Laura J. Esserman, Donald A. Berry. Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT227. doi:10.1158/1538-7445.AM2014-CT227

Calcilytics reduce airway hyperresponsiveness and inflammation and may represent effective asthma therapeutics.

Insulin stimulates the translocation fatty acid transport protein 1 (FATP1) to plasma membrane, and thus greater free fatty acid (FFA) uptake, in adipocyte cell models. Whether insulin stimulates greater FFA clearance into adipose tissue in vivo is unknown. We tested this hypothesis by comparing direct FFA storage in subcutaneous adipose tissue during insulin versus niacin-medicated suppression of lipolysis. We measured direct FFA storage in abdominal and femoral subcutaneous fat in 10 and 11 adults, respectively, during euglycemic hyperinsulinemia or after oral niacin to suppress FFA compared with 11 saline control experiments. Direct palmitate storage was assessed using a [U-13C]palmitate infusion to measure palmitate kinetics and an intravenous palmitate radiotracer bolus/timed biopsy. Plasma palmitate concentrations and flux were suppressed to 23 ± 3 and 26 ± 5 µmol ⋅ L−1 (P = 0.91) and 44 ± 4 and 39 ± 5 µmol ⋅ min−1 (P = 0.41) in the insulin and niacin groups, respectively, much less (P < 0.001) than the saline control group (102 ± 8 and 104 ± 12 µmol ⋅ min−1, respectively). In the insulin, niacin, and saline groups, abdominal palmitate storage rates were 0.25 ± 0.05 vs. 0.25 ± 0.07 vs. 0.32 ± 0.05 µmol ⋅ kg adipose lipid−1 ⋅ min−1, respectively (P = NS), and femoral adipose storage rates were 0.19 ± 0.06 vs. 0.20 ± 0.05 vs. 0.31 ± 0.05 µmol ⋅ kg adipose lipid−1 ⋅ min−1, respectively (P = NS). In conclusion, insulin does not increase FFA storage in adipose tissue compared with niacin, which suppresses lipolysis via a different pathway.

AbstractThe many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.

Abstract Epidemiologic studies have shown that diabetics receiving the biguanide metformin, as compared with sulfonylureas or insulin, have a lower incidence of breast cancer. Metformin increases levels of activated AMPK (AMP-activated protein kinase) and decreases circulating IGF-1; encouraging its potential use in both cancer prevention and therapeutic settings. In anticipation of clinical trials in nondiabetic women, the efficacy of metformin in nondiabetic rat and mouse mammary cancer models was evaluated. Metformin was administered by gavage or in the diet, at a human equivalent dose, in standard mammary cancer models: (i) methylnitrosourea (MNU)-induced estrogen receptor–positive (ER+) mammary cancers in rats, and (ii) MMTV-Neu/p53KO ER− (estrogen receptor–negative) mammary cancers in mice. In the MNU rat model, metformin dosing (150 or 50 mg/kg BW/d, by gavage) was ineffective in decreasing mammary cancer multiplicity, latency, or weight. Pharmacokinetic studies of metformin (150 mg/kg BW/d, by gavage) yielded plasma levels (Cmax and AUC) higher than humans taking 1.5 g/d. In rats bearing small palpable mammary cancers, short-term metformin (150 mg/kg BW/d) treatment increased levels of phospho-AMPK and phospho-p53 (Ser20), but failed to reduce Ki67 labeling or expression of proliferation-related genes. In the mouse model, dietary metformin (1,500 mg/kg diet) did not alter final cancer incidence, multiplicity, or weight. Metformin did not prevent mammary carcinogenesis in two mammary cancer models, raising questions about metformin efficacy in breast cancer in nondiabetic populations. Cancer Prev Res; 8(3); 231–9. ©2015 AACR.

ObjectiveAmyotrophic lateral sclerosis/parkinsonism–dementia complex has been described in Guam, Western Papua, and the Kii Peninsula of Japan. The etiology and pathogenesis of this complex neurodegenerative disease remains enigmatic.MethodsIn this study, we have used targeted genomic sequencing to evaluate the contribution of genetic variability in the pathogenesis of amyotrophic lateral sclerosis, parkinsonism, and dementia in Guamanian Chamorros.ResultsGenes previously linked to or associated with amyotrophic lateral sclerosis, parkinsonism, dementia, and related neurodegenerative syndromes were sequenced in Chamorro subjects living in the Mariana Islands. Homozygous PINK1 p.L347P, heterozygous DCTN1 p.T54I, FUS p.P431L, and HTT (42 CAG repeats) were identified as pathogenic mutations.InterpretationThe findings explain the clinical, pathologic, and genetic heterogeneity observed in some multi‐incident families and contribute to the excess incidence of neurodegeneration previously reported on Guam. Ann Neurol 2015;77:458–468