Citations

Abstract Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR translocations and activating mutations is implicated in many cancers, including CCA. FGFR2 translocations are the most common FGFR alterations, which occur in ~13% of pts with intrahepatic CCA and involve a variety of fusion partners/breakpoints. INCB054828 is a novel, orally available, selective inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activities (AACR 2015; Abstract 771). Methods: This phase 2, open-label trial will evaluate INCB054828 monotherapy in pts with advanced/metastatic or surgically unresectable CCA (Table; NCT02924376). Pts will be prescreened centrally for FGF/FGFR status and enrolled in the following cohorts prior to start of treatment: FGFR2 translocations (Cohort A); other FGF/FGFR alterations (Cohort B); no FGF/FGFR alterations (Cohort C; negative control for effects of FGF/FGFR alterations on objective response rate [ORR]). Pts must be aged ≥18 years, with Eastern Cooperative Oncology Group performance status ≤2, disease progression after ≥1 prior systemic therapy, and no prior use of selective FGFR inhibitors. Pts will self-administer INCB054828 orally at a starting dose of 13.5 mg once-daily on a 21-day cycle (2 weeks on; 1 week off); treatment will continue until disease progression or unacceptable toxicity. The primary endpoint will be ORR (complete or partial response per independent radiologic review committee using Response Evaluation Criteria in Solid Tumors v1.1) in pts with FGFR2 translocations (Cohort A). Secondary endpoints will include ORR in pts positive or negative for any FGF/FGFR alterations and duration of response, progression-free survival, overall survival, and safety (all cohorts). The study is currently open for enrollment (estimated primary completion date, April, 2018). Study DesignPrescreen for FGF/FGFR Status• Adults with metastatic/surgically unresectable cholangiocarcinoma with disease progression after ≥1 previous systemic treatment- FGFR2 translocations → cohort A (n~60)- Other FGF/FGFR alterations → cohort B (n~20)- No FGF/FGFR alterations → cohort C (n~20)Screen for eligibility criteria and patient characteristics• Eastern Cooperative Oncology Group performance status ≤2• Adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal [ULN; ≤2.5 × ULN for Gilbert syndrome or disease involving liver]; aminotransferases <2.5 × ULN [<5 × ULN with liver metastases])• Adequate renal function (creatinine clearance ≥30 mL/min; serum phosphate >institutional ULN; serum calcium >institutional normal range; potassium >institutional lower limit of normal)• Life expectancy ≥12 weeksEnroll and initiate INCB054828 treatment• Oral once daily dosing: 21-day (2-weeks-on/1-week-off) cycleStart response assessment after cycle 2• Stable disease/partial or complete response → continue treatment with restaging after cycle 4; imaging assessments increase to every 3 cycles after cycle 4• Disease progression → discontinue treatment; safety and survival follow-up Citation Format: Mitesh J. Borad, S. Lindsey Davis, Maeve A. Lowery, Ekaterine Asatiani, Christine F. Lihou, Huiling Zhen, Ghassan K. Abou-Alfa. Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 in patients (pts) with advanced, metastatic, or surgically unresectable cholangiocarcinoma (CCA) with inadequate response to prior therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT063. doi:10.1158/1538-7445.AM2017-CT063

Abstract Background: In vivo synergy with concurrent PI3-Kinase inhibition and PARP inhibition has been observed in BRCA-deficient and BRCA-proficient preclinical models of triple negative breast cancer (TNBC) and ovarian cancer (OC). A phase I trial of the oral pan-class I PI3-Kinase inhibitor BKM120 and the PARP inhibitor olaparib demonstrated anti-cancer activity in TNBC and OC, both in patients with and without germline BRCA1 and BRCA2 (BRCA) mutations. However, CNS toxicity (depression) and liver function test abnormalities limited dose escalation of BKM120 prompting evaluation of the alpha specific PI3-Kinase inhibitor BYL719 (which has no CNS toxicity) in combination with olaparib. Methods: Olaparib was administered twice daily (tablet formulation) and BYL719 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with primary objectives of defining the maximum tolerated dose (MTD) and recommended phase 2 dose of the combination of BYL719 and olaparib, and secondary objectives of defining toxicity, activity, and pharmacokinetic profiles of both agents. Eligibility included recurrent TNBC or high grade serous (HGS) OC, or any histology OC or breast cancer (BC) with presence of a known germline BRCA mutation, performance status of 0-1 and measurable/evaluable cancer. Patients with platinum sensitive or resistant or refractory OC were eligible and prior PARP inhibitor use was allowed. Dose-expansion cohorts at the MTD were enrolled for both BC and OC. Results: 46 patients (16 BC and 30 OC) have been enrolled in the study; 28 patients participated in the dose escalation portion of the study (4 BC and 24 OC). Two patients with OC did not receive study drugs because of ineligibility. MTD was defined as BYL719 200mg once daily and olaparib 200mg twice daily. Dose limiting toxicities included hyperglycemia, rash and fever with decreased neutrophil count. Four patients (3 OC and 1 BC) discontinued protocol therapy because of toxicity (2 for hyperglycemia, 1 for nausea and 1 for allergic reaction). Most common toxicities included nausea, hyperglycemia, fatigue, diarrhea and vomiting. At the MTD, 6 patients with OC and 12 patients with BC were enrolled into a dose expansion cohort. The OC expansion cohort has completed enrollment, while the BC cohort is still enrolling. Among patients with OC who received study drugs (28 patients, 26 (93%) with platinum resistant disease), objective response rate (ORR) by RECIST 1.1 was 36% (10/28 patients, all partial responses (PRs)). Median duration of response was 167 days (range 16-398 days); 5 of 10 patients with PR remain on treatment. ORR was 33% for patients with germline BRCA mutations and 31% for patients without germline BRCA mutations. Among patients without germline BRCA mutations with platinum resistant OC, ORR was 29%. Conclusions: Combined BYL719 and olaparib is feasible, and similar clinical benefit was observed in patients with and without germline BRCA mutations. The activity of this combination in OC patients without germline BRCA mutations and with platinum resistant disease was higher than expected from olaparib monotherapy and warrants further investigation. This work was funded in part by the Stand Up To Cancer Ovarian Dream Team. Clinical trial: NCT01623349. Citation Format: Panagiotis A. Konstantinopoulos, William T. Barry, Michael Birrer, Shannon N. Westin, Sarah Farooq, Karen Cadoo, Christin Whalen, Weixiu Luo, Hui Liu, Carol Aghajanian, David B. Solit, Gordon B. Mills, Barry S. Taylor, Helen Won, Michael F. Berger, Sangeetha Palakurthi, Joyce F. Liu, Lew Cantley, Scott H. Kaufmann, Elizabeth M. Swisher, Alan D. D'Andrea, Eric Winer, Gerburg M. Wulf, Ursula A. Matulonis. Phase I study of the alpha specific PI3-Kinase inhibitor BYL719 and the poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib in recurrent ovarian and breast cancer: Analysis of the dose escalation and ovarian cancer expansion cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT008. doi:10.1158/1538-7445.AM2017-CT008

Abstract LIN28 is well known as a RNA-binding protein and a suppressor of microRNA biogenesis, by selectively blocking the processing of let-7 precursors. It plays diverse functions in cellular reprogramming, development, metabolism and tumorigenesis. Many of these functions are executed through its ability to inhibit let-7 maturation. However, little is known about its function independent of let-7. Here we made zebrafish transgenic lines expressing high levels of either wild-type or mutant LIN28B (does not block the maturation of let-7) in the peripheral sympathetic nervous system driven by the dopamine beta-hydroxylase promoter. We bred these lines with a transgenic zebrafish line overexpressing the MYCN oncogene in these cells. Either wild-type or mutant LIN28B overexpression accelerated the onset and increased the penetrance of MYCN-induced neuroblastoma, despite the fact that only wild-type LIN28B blocked let-7 maturation compared to MYCN-only tumors. Mechanistically, both wild-type and mutant LIN28B overexpression enhanced MYCN-induced hyperplasia by increasing cell proliferation in the sympathoadrenal lineage. Further studies revealed that overexpression of either wild-type or mutant LIN28B resulted in hyperphosphorylation of AKT on both Ser473 and Thr308 in zebrafish tumors and also serum-deprived human neuroblastoma cell lines. Both wild-type and mutant LIN28B interacted with IGF2BP1, a known interactor that increases stability and translation of a subset of RNAs. We found IGF2 RNA levels to be increased in response to either form of LIN28B. Coincident with IGF2 overexpression, IGF1R was phosphorylated, providing an explanation for PI3K-AKT activation in LIN28B overexpressing cells. Finally, overexpression of a constitutively active, myristoylated murine Akt2 (myr-mAkt2) alone in zebrafish induced ganglioneuroma in the interregnal gland (the zebrafish equivalent of the human adrenal medulla), without a requirement for MCYN overexpression. Thus, our studies indicate that overexpression of LIN28B leads to AKT activation mediated through its interaction with IGF2BP1 and subsequent upregulation of IGF2. This pathway provides a mechanism underlying enhanced transformation in LIN28B overexpressing neuroblastomas, which is independent of the inhibitory activity of LIN28B on let-7 maturation. Citation Format: Ting Tao, John T. Powers, Hui Shi, Pavlos Missios, Antonio R. Perez-Atayde, Shizhen Zhu, George Q. Daley, Thomas A. Look. LIN28B-mediated let-7 independent activation of AKT promotes neuroblastoma pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1040. doi:10.1158/1538-7445.AM2017-1040

AbstractAutologous transplantation of mesenchymal stem cells (MSCs) is a viable option for the treatment of several diseases. Evidence indicates that MSCs release extracellular vesicles (EVs) and that EVs shuttle miRNAs to damaged parenchymal cells to activate an endogenous repair program. We hypothesize that comorbidities may interfere with the packaging of cargo in MSC‐derived EVs. Therefore, we examined whether metabolic syndrome (MetS) modulates the miRNA content packed within MSC‐derived EVs. MSCs were collected from swine abdominal adipose tissue after 16 weeks of lean or obese diet (n = 7 each). Next‐generation RNA sequencing of miRNAs (miRNA‐seq) was performed to identify miRNAs enriched in MSC‐derived EVs and their predicted target genes. Functional pathway analysis of the top 50 target genes of the top 4 miRNAs enriched in each group was performed using gene ontology analysis. Lean‐ and MetS‐EVs were enriched in, respectively, 14 and 8 distinct miRNAs. Target genes of miRNAs enriched in MetS‐EVs were implicated in the development of MetS and its complications, including diabetes‐related pathways, validated transcriptional targets of AP1 family members Fra1 and Fra2, Class A/1 (Rhodopsin‐like receptors), and Peptide ligand‐binding receptors. In contrast, miRNAs enriched in Lean EVs target primarily EphrinA‐EPHA and the Rho family of GTPases. MetS alters the miRNA content of EVs derived from porcine adipose tissue MSCs. These alterations could impair the efficacy and limit the therapeutic use of autologous MSCs in subjects with MetS. Our findings may assist in developing adequate regenerative strategies to preserve the reparative potency of MSCs in individuals with MetS. © 2017 International Society for Advancement of Cytometry

Abstract Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies. Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 noncancer diseases and traits. Results: After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (P < 0.003) genetic correlations between pancreatic and colorectal cancer (rg = 0.55, P = 0.003), lung and colorectal cancer (rg = 0.31, P = 0.001). We also found suggestive genetic correlations between lung and breast cancer (rg = 0.27, P = 0.009), and colorectal and breast cancer (rg = 0.22, P = 0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni-corrected P value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg = 0.41, P = 1.03 × 10−6). We also observed nominally significant genetic correlations between body mass index and all cancers except ovarian cancer. Conclusions: Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors. Impact: This study demonstrates modest genetic correlations between cancers; in particular, breast, colorectal, and lung cancer share some degree of genetic basis. Cancer Epidemiol Biomarkers Prev; 26(9); 1427–35. ©2017 AACR.

Objectives Recent studies have indicated that excessive fat may confound assessment of diffusion in organs with high fat content, such as the liver and breast. However, the extent of this effect in the kidney, which is not considered a major fat deposition site, remains unclear. This study tested the hypothesis that renal fat may impact diffusion-weighted imaging (DWI) parameters, and proposes a 3-compartment model (TCM) to circumvent this effect. Methods Using computer simulations, we investigated the effect of fat on assessment of apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM), and TCM-derived pure-diffusivity. We also investigated the influence of magnetic resonance repetition (TR) and echo time (TE) on DWI parameters as a result of variation in the relative contribution of the fat signal. Apparent diffusion coefficient, IVIM and TCM DWI parameters were calculated in domestic pigs fed a high-cholesterol (obese group) or normal diet (lean group), and correlated to renal histology. Intravoxel incoherent motion–derived pure-diffusivity was also compared among 15 essential hypertension patients classified by body mass index (BMI) (high vs normal). Finally, pure-diffusivity was calculated and compared in 8 patients with atherosclerotic renal artery stenosis (ARAS) and 5 healthy subjects using IVIM and TCM. Results Simulations showed that unaccounted fat results in the underestimation of IVIM-derived pure diffusivity. The underestimation increases as the fat fraction increases, with higher pace at lower fat contents. The underestimation was larger for shorter TR and longer TE values due to the enhancement of the relative contribution of the fat signal. Moreover, TCM, which incorporates highly diffusion-weighted images (b > 2500 s/mm2), could correct for fat-dependent underestimation. Animal studies in the lean and obese groups confirmed lower ADC and IVIM pure-diffusivity in obese versus lean pigs with otherwise healthy kidneys, whereas pure-diffusivity calculated using TCM were not different between the 2 groups. Similarly, essential hypertension patients with high BMI had lower ADC (1.9 vs 2.1 × 10−3 mm2/s) and pure-diffusivity (1.7 vs 1.9 × 10−3 mm2/s) than those with normal BMI. Pure-diffusivity calculated using IVIM was not different between the ARAS and healthy subjects, but TCM revealed significantly lower diffusivity in ARAS. Conclusions Excessive renal fat may cause underestimation of renal ADC and IVIM-derived pure-diffusivity, which may hinder detection of renal pathology. Models accounting for fat contribution may help reduce the variability of diffusivity calculated using DWI.

Abstract This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902. A phase 3 study is ongoing (#NCT01659658).