Eun Kee Song

Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer

PURPOSE Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel. PATIENTS AND METHODS In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m(2) per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS). RESULTS One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings. CONCLUSION Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.

Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas†

The current study was conducted to evaluate the efficacy and safety of everolimus in the treatment of patients with nonfunctioning neuroendocrine tumors (NETs) or pheochromocytomas/paragangliomas.

Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model.

Antiangiogenic therapy is commonly used for the treatment of colorectal cancer (CRC). Although patients derive some clinical benefit, treatment resistance inevitably occurs. The MET signaling pathway has been proposed to be a major contributor of resistance to antiangiogenic therapy. MET is upregulated in response to vascular endothelial growth factor pathway inhibition and plays an essential role in tumorigenesis and progression of tumors. In this study, we set out to determine the efficacy of cabozantinib in a preclinical CRC patient‐derived tumor xenograft model. We demonstrate potent inhibitory effects on tumor growth in 80% of tumors treated. The greatest antitumor effects were observed in tumors that possess a mutation in the PIK3CA gene. The underlying antitumor mechanisms of cabozantinib consisted of inhibition of angiogenesis and Akt activation and significantly decreased expression of genes involved in the PI3K pathway. These findings support further evaluation of cabozantinib in patients with CRC. PIK3CA mutation as a predictive biomarker of sensitivity is intriguing and warrants further elucidation. A clinical trial of cabozantinib in refractory metastatic CRC is being activated.

Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model.

Background:Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ-secretase inhibitor (GSI) PF-03084014.Methods:A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPjκ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting.Results:We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active β-catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours.Conclusion:This study provides evidence that inhibition of γ-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.

A NOTCH1 gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer

Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer (CRC) and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a portion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient‐derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1‐targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes.

Unusual manifestations of Taenia solium infestation

We present two rare cases of unusual manifestations of Taenia solium infestation. Taenia infestation usually causes abdominal pain and diarrhea in humans. But there have been no clinical reports of ascites, chronic diarrhea, and malabsorption due to Taenia solium without evidence of the ova or larvae of the parasites in stool examinations. Our first unusual case was in a 30-year-old woman with spontaneous pneumothorax, pleural effusion, and ascites; the second case was in a 67-year-old man with a 3-year history of diarrhea, weight loss, and indigestion. Both patients showed blood eosinophilia and positive serologic tests for Taenia solium. After antiparasitic agent administration, their symptoms resolved successfully.

Ramosetron Versus Ondansetron in Combination With Aprepitant and Dexamethasone for the Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: A Multicenter, Randomized Phase III Trial, KCSG PC10-21

BACKGROUND A combination of serotonin receptor (5-hydroxytryptamine receptor type 3) antagonists, NK-1 receptor antagonist, and steroid improves the complete response (CR) of chemotherapy-induced nausea and vomiting (CINV) in cancer patients. Ramosetrons efficacy in this triple combination regimen has not been investigated. This prospective, multicenter, single-blind, randomized, phase III study compares a combination of ramosetron, aprepitant, and dexamethasone (RAD) with a combination of ondansetron, aprepitant, and dexamethasone (OAD) to prove the noninferiority of RAD in controlling highly emetogenic CINV. METHODS Aprepitant and dexamethasone were orally administered for both arms. Ramosetron and ondansetron were intravenously given to the RAD and OAD groups. The primary endpoint was no vomiting and retching and no need for rescue medication during the acute period (day 1); the noninferiority margin was -15%. RESULTS A total of 299 modified intention-to-treat cancer patients who received RAD (144 patients) and OAD (155 patients) were eligible for the efficacy analysis. The CR rates of RAD versus OAD were 97.2% versus 93.6% during the acute period, 77.8% versus 73.6% during the delayed period (day 2-5), and 77.1% versus 71.6% during the overall period. Furthermore, RAD was noninferior to OAD in subgroups stratified by age, cancer type, chemotherapeutic agents, and schedule. Repeated measures analysis showed that in male patients, RAD was superior to OAD. Profiles of adverse events were similar in both groups. CONCLUSION RAD is as effective and tolerable as OAD for CINV prevention in patients receiving highly emetogenic chemotherapy. Ramosetron could be considered one of the best partners for aprepitant.

Phase II study of S‐1 and irinotecan combination chemotherapy as a first‐line therapy for patients with advanced gastric cancer. Korean Cancer Study Group Protocol ST05‐02

Background:  Irinotecan plus intravenous 5‐fluorouracil (5‐FU) with leucovorin is effective against gastrointestinal cancer. S‐1 is an oral fluoropyrimidine derivative and has a high response rate of about 40% for patients with advanced gastric cancer (AGC). We evaluated the antitumor activity and toxicities of an S‐1 and irinotecan combination as a first‐line therapy for patients with AGC.

Evaluation of the efficacy of dasatinib, a Src/Abl inhibitor, in colorectal cancer cell lines and explant mouse model

Background Dysregulation of the Src pathway has been shown to be important at various stages of cancer. Dasatinib is a potent Src/Abl inhibitor and has demonstrated to have anti-proliferative and anti-invasive activity in many preclinical models. The objective of this study was to determine the anti-tumor activity of dasatinib using in vitro and in vivo preclinical colorectal (CRC) models. Methods CRC cell lines and patient-derived tumor explant (PDX) models were used to investigate the efficacy of dasatinib. We treated 50 CRC cell lines with dasatinib for 72 hours and proliferation was assayed by a sulforhodamine B (SRB) assay; an IC50 ≤ 0.08 μmol/L was considered sensitive. We treated 17 patient-derived CRC explants with dasatinib (50 mg/kg/day, administered once-daily) for 28 days to determine in vivo efficacy. Tumor growth inhibition (TGI) ≥ 50% was considered sensitive. Results We found that 8 out of 50 CRC cell lines reached an IC50 ≤ 0.08 μmol/L with dasatinib treatment. In addition, of 17 CRC explants grown in the xenograft mouse model, 2 showed sensitivity to dasatinib. The anti-tumor effects observed in this study were a result of G1 cell cycle arrest as the dasatinib sensitive CRC cell lines exhibited G1 inhibition. Moreover, those CRC cell lines that were responsive (0.08 μmol/L) to treatment demonstrated a significant baseline increase in Src and FAK gene expression. Conclusion Dasatinib demonstrated significant anti-proliferative activity in a subset of CRC cell lines in vitro, especially in those with increased Src expression at baseline, but only showed modest efficacy in CRC explants. Dasatinib is currently being studied in combination with chemotherapy in patients with advanced CRC, as its use as a single agent appears limited.

Abstract B30: KRAS wild type tumors exhibit increased efficacy to the combination of AZ1 (a tankyrase inhibitor) + irinotecan in a patient-derived CRC explant model.

Background: Dysregulation of the canonical Wnt signaling pathway has been implicated in colorectal cancer (CRC) development as well as incipient stages of malignant transformation. An important regulator of the Wnt pathway are tankyrases that function in reducing Axin2 levels which is an essential protein in the β-catenin destruction complex. Targeting this pathway with a potent tankyrase inhibitor presents a plausible approach in drug development. In this study, we evaluated the antitumor effects AZ1 (a novel tankyrase 1/2 inhibitor which also carries PARP1 activity) as a single agent and in combination with irinotecan in our patient derived CRC explant xenograft models. Methods: Twenty patient derived CRC explant xenografts were treated with vehicle, AZ1 (50mg/kg/day), irinotecan (30mg/kg/week) or AZ1 (50mg/kg/day) + irinotecan (30mg/kg/week) for 28 days. Pharmacokinetic effect of AZ1 was determined in plasma and tumor over 24h. Both pharmacodynamic effects (Axin2 levels) and changes in biomarkers relevant to the Wnt pathway were determined by Western blotting. Intra-nuclear β-catenin levels were evaluated by immunohistochemistry. A tumor growth index (TGI) was calculated as the ratio in tumour volumes in the treated animals and the control animals (T/C) on the last day of drug treatment to determine efficacy. TGI≤ 50% was considered sensitive and TGI > 50% was resistant. Results: Three out of 20 CRC explants showed some tumour growth inhibition with AZ1. In animals bearing CRC40 xenografts, AZ1 showed a Tmax of 1 hour in plasma and 30 minutes in tumor. In addition, Axin2 stabilization post AZ1 started 15 minutes after drug administration, with the maximum stabilization observed at 8 hours. Treatment with AZ1 + irinotecan resulted in a greater anti-tumor effect (achieving stasis or better) than either agent alone in 4 out of 20 CRC xenografts. A significant association (fisher exact test: p= 0.007) was identified between combinational sensitivity and KRAS wild type. Evaluation of tumors after treatment showed marked stabilization of Tankyrase 1/2 and Axin2; however, active β-catenin levels were not changed. Also, there were no changes to intra-nuclear β-catenin (IHC) levels after treatment. Interestingly, NuMa, a protein involved in maintenance of the mitotic spindle and a target of Tankyrase 1/2 increased following irinotecan in 3 models, 2 showing a combination effect and 1 which did not. Numa levels decreased with the combination of AZ1 and irinotecan compared to irinotecan alone in 2 models showing a significant combination effect. Conclusion: Combination AZ1 and irinotecan achieved greater anti-tumor effect compared to monotherapy in 4 out of 20 CRC xenografts. Activity was limited to CRC xenografts with KRAS WT status. Further studies are warranted to validate these findings in KRAS WT patients and to understanding the specific mechanisms in tumors that responded to combinational therapy. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B30. Citation Format: WM Tai, Kevin Quackenbush, Alicia Purkey, Stacey Bagby, Wells Messersmith, Eun Kee Song, Todd Pitts, John J. Arcaroli. KRAS wild type tumors exhibit increased efficacy to the combination of AZ1 (a tankyrase inhibitor) + irinotecan in a patient-derived CRC explant model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B30.