bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 741: Combined inhibition of MDM2 and MEK for KRAS mutant non-small cell lung cancer
Authors: Hata Aaron N. , Archibald Hannah L. , Gomez-Caraballo Maria D. , DeBussche Laurent R. , Sidhu Sukhvinder , Watters James , Engelman Jeffrey A.
Published: May 2015

There are currently no effective targeted therapies for KRAS mutant NSCLC. Combination drug strategies that target downstream pathways activated by mutant KRAS are currently being investigated, however efficacy may be limited by inability to induce a sufficient apoptotic response. MDM-2 (murine double minute 2) is a ubiquitin ligase that negatively regulates p53 function by promoting its degradation. Inhibitors of the MDM2-p53 interaction lead to p53 activation and transcription of genes promoting cell cycle arrest and apoptosis. We investigated the efficacy of combined MEK and MDM2 inhibition for KRAS mutant NSCLC. In KRAS mutant NSCLC cell lines with wild-type p53, pimasertib (MEKi) and SAR405838 (MDM-2i) led to upregulation of BIM and PUMA respectively. Induction of apoptosis and cell cycle arrest correlated with in vitro efficacy, and the combination exhibited marked in vivo activity against KRAS mutant p53 wild-type NSCLC xenograft tumors. These studies provide rationale for future clinical investigation of combined MEK and MDM-2 inhibition for KRAS mutant NSCLC.

Citation Format: Aaron N. Hata, Hannah L. Archibald, Maria D. Gomez-Caraballo, Laurent R. DeBussche, Sukhvinder Sidhu, James Watters, Jeffrey A. Engelman. Combined inhibition of MDM2 and MEK for KRAS mutant non-small cell lung cancer. [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 741. doi:10.1158/1538-7445.AM2014-741
Abstract 9: An angiogenic function for E-cadherin in ovarian cancer
Authors: Tang Maggie Kei Shuen , Wong Alice Sze Tsai
Published: May 2015

The loss of E-cadherin, a cell-cell adhesion molecule, is a well-established marker for metastasis of cancer. Although E-cadherin is synthesized as a transmembrane molecule, it can be cleaved of the ectodomain and released in a soluble form (sE-cad), and this accounts a key mechanism for a rapid reduction of functional E-cadherin at the cell surface. Yet, very little is known about how this important protein dictates the metastasis of these tumors. In ovarian cancer, a highly metastatic tumor that is rapidly lethal, sE-cad is highly expressed in the serum and metastatic ascites of ovarian carcinoma patients. Despite many studies focused on the role of E-cadherin loss in weakening cell-cell adhesion, whether sE-cad has biological activity in itself remain virtually unknown. Here we show for the first time that sE-cad can transduce angiogenic signals. sE-cad was also present in the culture supernatant of ovarian cancer lines. sE-cad of supernatant and a recombinant sE-cad-Fc chimera potently stimulated the migration of, permeability, and tubulogenesis by human umbilical vein endothelial cells in vitro. sE-cad also promoted functional neovascularization in a Matrigel implant model in vivo. These effects could be reversed by neutralizing anti-sE-cad, confirming that the effects were sE-cad specific. In addition, we found that sE-cad bound to VE-cadherin, an effect mediated through the phosphatidylinositol 3-kinase/Akt-β-catenin pathway. These results unravel a new and important piece to the complex biology of tumor angiogenesis and metastasis, and provide insights of novel mechanisms regulating angiogenesis (This study was supported by RGC grant HKU781013).

Citation Format: Maggie Kei Shuen Tang, Alice Sze Tsai Wong. An angiogenic function for E-cadherin in ovarian cancer. [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 9. doi:10.1158/1538-7445.AM2014-9
Abstract 983: Intratumor heterogeneity in non-small cell lung cancer inferred by multi-region exome sequencing
Authors: Bruin Elza D. , McGranahan Nicholas , Yates Lucy , Jamal-Hanjani Mariam , Salm Max , Mitter Richard , Shafi Seema , Murugaesu Nirupa , Rowan Andrew , Gerlinger Marco , Wedge David , Horswell Stuart , Varela Ignacio , Tom Warren , Parikh Chaitali , Harkins Timothy , Lee Clarence , Matthews Nik , Stewart Aengus , Campbell Peter , Swanton Charles
Published: May 2015

Lung cancer is the most common cancer worldwide, and a leading cause of cancer-related death. Despite improvements in molecular diagnosis and targeted therapies, the 5-years overall survival remains poor. To obtain a better insight into the genetic architecture of the most common type of lung cancer, non-small lung cancer (NSCLC), we performed multi-region DNA sequencing on 7 resected NSCLC samples.

Ultra-deep sequencing of a comprehensive cancer gene panel and whole-exome sequencing revealed intratumor heterogeneity in all samples, with several putative tumor driver mutations present in some but not all regions of a tumor. Phylogenetic tree analyses based on non-synonymous mutations revealed a branched evolution pattern in all tumors. An adenosquamous tumor showed striking intratumor heterogeneity, with only a third of all non-synonymous mutations shared across all tumor regions, and clear separation of adenocarcinoma and squamous cell carcinoma tumor regions in the remaining two-third of the mutations. Our multi-region exome sequencing data also revealed regional differences in DNA copy number alterations. Some tumors, relatively homogeneous in terms of mutations, displayed high levels of intratumor heterogeneity in terms of DNA copy number changes, indicating the presence of distinct patterns of intratumor heterogeneity that might contribute to disease progression in different tumours.

Overall, our multi-region deep exome sequencing data revealed intratumor heterogeneity in NSCLC, demonstrating branched evolution, both in terms of non-synoymous mutations and DNA copy number alterations, which has important implications for our understanding of the clonal evolution of NSCLC.

Citation Format: Elza De Bruin, Nicholas McGranahan, Lucy Yates, Mariam Jamal-Hanjani, Max Salm, Richard Mitter, Seema Shafi, Nirupa Murugaesu, Andrew Rowan, Marco Gerlinger, David Wedge, Stuart Horswell, Ignacio Varela, Warren Tom, Chaitali Parikh, Timothy Harkins, Clarence Lee, Nik Matthews, Aengus Stewart, Peter Campbell, Charles Swanton. Intratumor heterogeneity in non-small cell lung cancer inferred by multi-region exome sequencing. [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 983. doi:10.1158/1538-7445.AM2014-983
Abstract 99: Wnt signaling promotes tumor propagation in a mouse model of lung adenocarcinoma
Authors: Tammela Tuomas , Kerper Natanya , Xue Wen , Joshi Nikhil , Katajisto Pekka , Jacks Tyler
Published: May 2015

The considerable variability within tissue microenvironments as well as the multiclonality of cancers leads to heterogeneity within tumors, increasing the probablility of cellular states that promote resistance to therapy and eventually lead to reconstitution of the tumor by treatment-resistant cancer cells, which in some case have properties of normal tissue stem cells. Wnt signals are important in the maintenance of stem cells in various epithelial tissues, including in lung development and regeneration. We hypothesized that Wnt signals would also contribute to hierarchial organization of KrasG12D and KrasG12D; tp53Δ/Δ mouse lung adenocarcinomas. Indeed, rare cells with nuclear βeta-catenin were detected in mouse tumors in vivo. Stimulating KP mouse lung adenocarcinoma cells with recombinant Wnt3a promoted their spheroid-forming ability in a 3-dimensional Matrigel culture system, whereas RNAi or small-molecule inhibitors targeting Porcupine, an enzyme required for post-translational palmitoylation of Wnt, suppressed tumor initiation in vitro and in vivo. Interestingly, either the stimulation or inhibition of the Wnt signaling pathway had no effect on growth of KP lung cancer cells in standard 2-dimensional cell culture, suggesting that Wnt signaling qualitatively modulates the cellular phenotype instead of controlling cell proliferation. We propose that targeting the Wnt signaling pathway can stimulate re-differentiation of lung adenocarcinoma cells, which may render them more sensitive to conventional anti-tumor therapies.

Citation Format: Tuomas Tammela, Natanya Kerper, Wen Xue, Nikhil Joshi, Pekka Katajisto, Tyler Jacks. Wnt signaling promotes tumor propagation in a mouse model of lung adenocarcinoma. [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 99. doi:10.1158/1538-7445.AM2014-99
Abstract CT223: Dendritic cells pulsed with Wilms′ tumor gene 1 (WT1)-specific and MHC class I and II-restricted epitopes with gemcitabine induce antitumor immune responses in patients with advanced pancreatic cancer
Authors: Koido Shigeo , Homma Sadamu , Okamoto Masato , Mori Masako , Yoshizaki Shinji , Takakura Kazuki , Hayashi Kazumi , Kan Shin , Ishidao Takafumi , Yusa Sei-ichi , Shimodaira Shigetaka , Uchiyama Kan , Kajihara Mikio , Imazu Hiroo , Arakawa Hiroshi , Ohkusa Toshifumi , Tajiri Hisao
Published: May 2015

Wilms' tumor gene 1 (WT1) protein is an attractive target for cancer immunotherapy. To evaluate whether dendritic cells (DCs) pulsed with WT1-specific and MHC class I and II-restricted epitopes in combination with gemcitabine induce antitumor immune responses and improve clinical outcome in patients with advanced pancreatic cancer, we investigated the clinical and immunologic responses to the chemoimmunotherapy. Ten pancreatic cancer patients with stage IV and HLA positive for HLA-A*02:01, A*02:06, A*24:02, DRB1*04:05, DRB1*08:03, DRB1*15:02, DRB1*15:01, DPB1*09:01, or DPB1*05:01 were enrolled in this study. Patients first received gemcitabine on days 1, 8, and 15, followed by intradermal vaccinations with DCs pulsed with MHC class I or II alone (n=3), or MHC-I/II-restricted WT1 peptides (n=7) depending on their HLA biweekly and gemcitabine on days 1, 8, and 15 of a 28-day cycle. In 4 of 7 patients vaccinated with MHC-I/II pulsed DCs and none of 3 patients vaccinated with MHC-I or -II pulsed DCs, we detected WT1 peptide-specific delayed-type hypersensitivity (DTH). Among ten enrolled patients, DTH-positive patients showed significantly improved clinical outcome, compared with negative patients. Moreover, longer survivors featured a higher frequency of memory-phenotype in WT1-specific cytotoxic T-lymphocytes after vaccination with MHC-I/II pulsed DCs. In conclusion, the combination therapy was well-tolerated and activation of WT1-specific immune responses may be associated with improved clinical responses for patients with advanced pancreatic cancer.

Citation Format: Shigeo Koido, Sadamu Homma, Masato Okamoto, Masako Mori, Shinji Yoshizaki, Kazuki Takakura, Kazumi Hayashi, Shin Kan, Takafumi Ishidao, Sei-ichi Yusa, Shigetaka Shimodaira, Kan Uchiyama, Mikio Kajihara, Hiroo Imazu, Hiroshi Arakawa, Toshifumi Ohkusa, Hisao Tajiri. Dendritic cells pulsed with Wilms′ tumor gene 1 (WT1)-specific and MHC class I and II-restricted epitopes with gemcitabine induce antitumor immune responses in patients with advanced pancreatic cancer. [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 CT223. doi:10.1158/1538-7445.AM2014-CT223
Abstract CT302: A phase II clinical trial of weekly paclitaxel and carboplatin in combination with panitumumab in metastatic or recurrent breast cancer patients with triple negative disease
Authors: Cowherd Stacy , Melin Susan , Akman Steven , Cole John , Lawrence Julia
Published: May 2015

Purpose: Metastatic triple negative breast cancer is an unmet need in oncology. A targeted therapy for triple negative breast cancer has not been found so metastases are treated with chemotherapy as a single agent or in combination. The epidermal growth factor receptor (EGFR) is frequently over-expressed in triple negative breast cancer. This EGFR receptor can be targeted with agents such as cetuximab or panitumumab. We designed a single-arm clinical trial to investigate the activity of panitumumab in combination with carboplatin and paclitaxel in women with triple negative breast cancer.

Patients and Methods: Patients with metastatic disease and who had received no greater than one prior chemotherapy regimen were eligible for the study. Patients received paclitaxel 80mg/m^2 and carboplatin with AUC 2 on days 1, 8, and 15. In addition they received panitumumab 6mg/kg on days 1 and 15. The primary endpoint was overall response rate. We evaluated patients for toxicity prior to each cycle. We also subtyped the breast tumor specimens using microarray into basal-like, Her-2 enriched, luminal A, luminal B, and normal-like to assess for differential response to therapy among these subtypes.

Results: We enrolled 14 patients into the study at two sites (Wake Forest University Baptist Medical Center and Ochsner Medical Center). The average age of enrolled patients was 54.1 years. Nine out of the 14 women were African American and 5 patients were Caucasian. The median number of cycles received by the cohort was 3.5 (1-9) with median time to progression of 98 days. Common grade 3 and 4 adverse events included lymphopenia in 5 patients and neutropenia in 9 patients. Seven participants experienced grade 1/2 mucositis and two participants had grade 3 mucositis. Seven patients experienced grade 1/2 acneiform rash. Response to therapy based on tumor subtype (basal-like, Her-2 enriched, luminal A, luminal B, or normal-like) will also be presented, data in progress.

Conclusion: Adding the EGFR inhibitor panitumumab to carboplatin/paclitaxel was a well-tolerated and effective therapy for metastatic triple negative breast cancer. This combination could be most appropriate for certain subtypes of triple negative disease.

Citation Format: Stacy Cowherd, Susan Melin, Steven Akman, John Cole, Julia Lawrence. A phase II clinical trial of weekly paclitaxel and carboplatin in combination with panitumumab in metastatic or recurrent breast cancer patients with triple negative disease. [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 CT302. doi:10.1158/1538-7445.AM2014-CT302
Abstract CT318: FOLFOXIRI+B-mab showed powerful effect as preoperative chemotherapy for multiple liver metastases of colorectal cancer
Authors: Ichikawa Yasushi , Goto Ayumu , Kobayashi Noritoshi , Tokuhisa Motohiko , Ishikawa Takashi , Ishibe Atsushi , Watanabe Kazuteru , Nojiri Kazunori , Kumamoto Yoshibumi , Takeda kazuhisa , Ota Mitsuyoshi , Akiyama Hirotoshi , Tanaka Kuniya , Endo Itaru
Published: May 2015

Background; R0 resection for liver metastases of colorectal cancer is one of the promising treatment to improve prognosis of advanced colorectal cancer. Powerful regimen FOLFOXIRI including 3 cytotoxic drugs; 5FU, irinotecan and oxaliplatin was reported as promising treatment for advanced colorectal cancer (J Clin Oncol 2007; 25: 1670-76). In our department Phase I/II study of FOLFOXIRI+B-mab including fluoroiuracil/oxaliplatin/irinotecan/bevacizumab for advanced liver metastases of colorectal cancer as pre-operative chemotherapy has been conducted now, and Phase II was on going. In this study, we report effect and safety of FOLFOXIRI+B-mab.

Methods: The study was designed as a single-arm, open-label phase I/II trial. Phase I was conducted to decide tolerated dose (MTD) of irinotecan and 150 mg/m2 was decided as recommended dose. Patients who are colorectal cancer with 4 or more liver metastases and no other distant metastases are included. The regimen includes bevacizumab; 5 mg/kg, irinotecan; 150 mg/m2, oxaliplatin; 85 mg/m2, l-LV; 200 mg/m2, 5FU; 400 mg/m2 administered on day 1, followed by 5FU; 2400 mg/m2 continuously administered for 46 hours. R0 resection rate of liver metastases as primary endpoint will be evaluated.

Results: Currently, 16 patients were enrolled. Two patients dropped out because of grade 3 diarrhea and grade 3 thromboembolism. One patient is waiting for liver resection and R0 resection of liver metastases was performed for 9 patients. In the 14 patients excluding 2 drop out, 13 showed PR and average of reduction rate was 51%. There was no pathological CR in the 9 patients who was performed R0 resection. There was no severe postoperative complication in them.

Conclusion: This regimen is safe and shows high PR rate. So, the regimen is effective and improve R0 resection rate for multiple liver metastases of colorectal cancer. Further investigation of this study is still ongoing now.

Citation Format: Yasushi Ichikawa, Ayumu Goto, Noritoshi Kobayashi, Motohiko Tokuhisa, Takashi Ishikawa, Atsushi Ishibe, Kazuteru Watanabe, Kazunori Nojiri, Yoshibumi Kumamoto, kazuhisa Takeda, Mitsuyoshi Ota, Hirotoshi Akiyama, Kuniya Tanaka, Itaru Endo. FOLFOXIRI+B-mab showed powerful effect as preoperative chemotherapy for multiple liver metastases of colorectal cancer. [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 CT318. doi:10.1158/1538-7445.AM2014-CT318
Abstract CT334: Pazopanib as third-line therapy for metastatic renal cell carcinoma: Clinical efficacy and temporal analysis of cytokine profile
Authors: Pal Sumanta K. , Hossain Dewan Md Sakib , Zhang Qifang , Gao Chan , Jones Jeremy O. , Frankel Paul H. , Figlin Robert A. , Kortylewski Marcin
Published: May 2015

Background: Pazopanib was assessed in a phase III study conducted in patients (pts) with mRCC who were either cytokine-refractory or treatment-naïve, and clinical outcomes with pazopanib have been associated with a specific immunologic profile (IP). The activity of pazopanib in the third-line setting and temporal changes in molecular profile during therapy are poorly understood, however.

Methods: Eligibility was limited to pts with 2 prior lines of therapy (including at least 1 VEGF-directed therapy), ECOG PS 0-2, and clear cell histology. Pts received pazopanib 800 mg/daily on a 28d cycle. A Simon MinMax 2-stage design was employed, with 80% power of declaring an encouraging overall response rate (ORR) of 23% (type I error=10%). IPs were assessed monthly on a Luminex platform using the Human Cytokine 30-plex Cytokine Immunoassay (Invitrogen).

Results: 28 pts were enrolled with a median age of 63 (range, 45-86). In the pre-specified intent-to-treat analysis, 12/28 pts (43%) had a confirmed response (1 CR, 11 PR), with 1 additional unconfirmed PR. Median progression-free survival for the cohort was 17.4 mos (95% CI 14.7-NR). No grade 4 treatment-related toxicities were observed. The most common grade 3 toxicities included hypertension (46%) and proteinuria (14%). Amongst patients still on therapy at 6 months and 12 months, responders had lower levels of HGF, VEGF, IL-6, IL-8 and soluble IL-2R (P<0.05 for each). Non-responders also showed increased numbers of myeloid-derived suppressor cells (MDSCs) at both time intervals. Phenotypic and functional studies confirmed that MDSCs from these mRCC patients were granulocytic.

Conclusions: The ORR observed with pazopanib in the current study is the highest to date in a third-line trial in mRCC. Differences in cytokine profile and granulocytic MDSC quantity between responders and non-responders suggest that the mechanism of pazopanib resistance is at least partly related to generation of systemic tumor immune tolerance.

Citation Format: Sumanta K. Pal, Dewan Md Sakib Hossain, Qifang Zhang, Chan Gao, Jeremy O. Jones, Paul H. Frankel, Robert A. Figlin, Marcin Kortylewski. Pazopanib as third-line therapy for metastatic renal cell carcinoma: Clinical efficacy and temporal analysis of cytokine profile. [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 CT334. doi:10.1158/1538-7445.AM2014-CT334
Abstract CT342: Phase I/II study of gefitinib in combination with vorinostat in patients with advanced non-small cell lung cancer (NSCLC) who progressed on prior chemotherapy
Authors: Han Ji-Youn , Lee Soo Hyun , Yun Tak , Lee Young Jooo , Hwang Kum Hui , Ryu Sunah , Kim Heung Tae , Lee Jin Soo
Published: May 2015

Background: Gefitinib has shown marked efficacy in EGFR-mutant NSCLC. However, the development of acquired resistance is inevitable. Additionally, its therapeutic effect in EGFR-wild type NSCLC is controversial. Vorinostat, a histone deacetylase inhibitor, has shown to overcome resistance to gefitinib. We performed a phase I/II study combining gefitinib with vorinostat in previously treated patients with advanced NSCLC.

Methods: A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: gefitinib 250/day on days 1 through 28 and vorinostat on days 1-7 and 15-21 at 200, 300 and 400mg/day every 28 days. Phase II eligibility included advanced NSCLC, ≤2 line prior therapy, PS 0-2, adequate organ function. The primary endpoint was to determine the median progression-free survival (PFS) (null hypothesis 3.5 months, alternative hypothesis 6.5 months).

Results: Planned dose escalation was completed without reaching the MTD. The RP2D was gefitinib 250mg and vorinostat 400mg. Fifty-two patients were enrolled and treated in this study (43 in phase II). The median age was 59 years (range, 39 to 79 years), 30 were male, 48 had adenocarcinoma, 29 were never smokers, 31 had one prior regimen and 12 had two prior regimens; 21 had sensitive EGFR mutations, 3 had resistant exon 20 mutations and 5 had KRAS mutations. The most common adverse events were mild or moderate diarrhea, anorexia and anemia. In 43 assessable patients in phase II, there were 16 partial responses, 6 stable disease. The median PFS was 3.4 months; overall survival (OS) was 20.3 months. In patient harboring EGFR mutations, response rate (RR) was 88%, median PFS was 9.3 months and median OS was 22.6 months.

Conclusions Gefitinib 250mg daily with biweekly vorinostat 400 mg/day was feasible and well tolerated. In unselected patient population, this combination dose not improved PFS compared with historical control of single gefitinib. However, in EGFR-mutant NSCLC, this combination may improve RR and survival compared with historical control of gefitinib in previously treated EGFR-mutant NSCLC.

Citation Format: Ji-Youn Han, Soo Hyun Lee, Tak Yun, Young Jooo Lee, Kum Hui Hwang, Sunah Ryu, Heung Tae Kim, Jin Soo Lee. Phase I/II study of gefitinib in combination with vorinostat in patients with advanced non-small cell lung cancer (NSCLC) who progressed on prior chemotherapy. [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 CT342. doi:10.1158/1538-7445.AM2014-CT342
Abstract CT407: Phase I study of preoperative continuous 5-fu and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma
Authors: Kim Richard , Jiang Kun , Zhao Xiuhua , Chen Dung-Tsa , Campos Tiffany , Hoffe Sara , Shridhar Ravi , Shibata David
Published: May 2015

Background: Preoperative treatment with fluoropyrimidine-based chemoradiotherapy is considered standard therapy for locally advanced rectal cancer( T3, T4 or N1). Sorafenib is an inhibitor of ras/raf, PDFGR and VEGFR with synergistic activity with radiation. The phase I trial evaluated the safety and efficacy of sorafenib in combination with infusional 5-FU and radiation

Methods: Patients with stage II or III patients confirmed by EUS and CT scan were recruited in cohorts of 3 patients per dose level (DL). A 3+3 dose escalation design was used. On all dose levels RT was given in 25 fractions at 1.8Gy (45Gy) day 1- 5. Surgery was done 6-10 weeks after the completion of neoadjuvant treatment.

Results: At Moffitt Cancer we enrolled 12 patients in 4 cohorts. 8 females(67%) and 4 males(33%); Median age is 55(range: 40-72). After observing toxicity in first cohort ( 2 pts with with G2 and G3 skin toxicity and 1 pt with G2 mucositis) which required dose interruptions, amendment was made to change the schedule of chemotherapy and sorafenib to days 1-5 instead of daily. After the amendment, hypertension was the only grade III toxicity observed. 2 patients had G3 hypertension at 200mg adjusted dose(day1-5); 1 patient had G3 hypertension at 400 mg PO BID dose level and no grade IV toxicities were seen. No perioperative complications related to the study drugs were seen. 2 patients never went to surgery due to patient refusal. KRAS testing information was available on 10 patients. pCR rate was 30 % and downstaging was observed in 80% of the patients. pCR was 50% in patients with Kras mutant tumors ( 2/4 pts)

Conclusion: After changing the schedule of the chemotherapy, the regimen was very well tolerated. pCR and downstaging rate of the tumor seems to be encouraging. Plan is to open up an expansion cohort at DL3 to gather more safety and efficacy data.

Schedule of sorafenib dose escalationDose level ( 3 patients each)Sorafenib5-FU infusion Rate (mg/m2/24hrsDL 1 before amendment200mg PO QD225 on day 1-7 for 5½ weeksDL 1 after amendment200mg PO QD( Day1-5)225 on day 1-5 for 5½ weeksDL 2 after amendment400mg PO QD( Day1-5)225 on day 1-5 for 5½ weeksDL 3 after amendment400mg PO BID( Day1-5)225 on day 1-5 for 5½ weeks

Citation Format: Richard Kim, Kun Jiang, Xiuhua Zhao, Dung-Tsa Chen, Tiffany Campos, Sara Hoffe, Ravi Shridhar, David Shibata. Phase I study of preoperative continuous 5-fu and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma. [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 CT407. doi:10.1158/1538-7445.AM2014-CT407
Abstract CT420: An open label pilot study of NovoTTF Therapy concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma (NCT01971281)
Authors: Weinberg Uri , Kirson Eilon D. , Farber Ori , Giladi Moshe , Palti Yoram
Published: May 2015

Background: NovoTTF Therapy is a non-invasive, anti-mitotic treatment modality, based on low intensity alternating electric fields. Tumor Treating Fields (TTFields) interfere with two steps during mitosis: The formation of the mitotic spindle (metaphase), and the translocation of charged organelles (anaphase). TTFields inhibit proliferation of pancreatic cell lines in vitro, and inhibit pancreatic tumor growth in vivo, alone and in combination with gemcitabine. NovoTTF Therapy applied to the brain in recurrent GBM patients demonstrated an anti-tumoral effect with minimal toxicity and better quality of life, compared to chemotherapy (Stupp et al, 2012). Being a regional treatment, TTFields can potentially inhibit the primary tumor as well as major metastatic sites of pancreatic adenocarcinoma.

Objectives: the current trial is designed to study the safety, tolerability and efficacy of NovoTTF therapy applied to the abdomen concomitant to the standard care gemcitabine treatment, in patients suffering from advanced pancreatic adenocarcinoma.

Endpoints: severity and frequency of adverse events associated with the experimental treatment (primary), progression free survival (PFS), 6-month PFS rate, overall survival, overall response rate, compliance with NovoTTF Therapy (secondary)

Treatments: Gemcitabine 1000 mg/m^2 over 30 minute infusion once weekly for up to 7 weeks, followed by a week rest from treatment. Subsequent cycles will consist of once weekly infusions on days 1, 8, 15 every 28 days. Continuous NovoTTF Therapy at a frequency of 150 kHz will be administered to the abdomen, in order to cover the region of primary tumor and main metastatic sites. The fields will be applied in two perpendicular directions at a maximal intensity of 1414 mA RMS, using highly insulated Transducer Arrays connected to a portable, battery-operated electric field generator. TTFields will be administered for at least 18 hours a day until radiological disease progression.

Major eligibility criteria: unresectable, pathologically confirmed, locally advanced/metastatic pancreatic adenocarcinoma, measurable/assessable disease, ECOG score 0-1, no prior chemotherapy or radiation, no implantable electronic medical devices.

Citation Format: Uri Weinberg, Eilon D. Kirson, Ori Farber, Moshe Giladi, Yoram Palti. An open label pilot study of NovoTTF Therapy concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma (NCT01971281). [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 CT420. doi:10.1158/1538-7445.AM2014-CT420
Abstract DDT01-01: Discovery of CGM097 as a novel Mdm2 inhibitor
Authors: Masuya Keiichi , Furet Pascal , Stutz Stefan , Holzer Philipp , Pissot-Soldmann Carole , Buschmann Nicole , Valat Thérèse , Ferretti Stéphane , Ruetz Stephan , Rynn Caroline , Berghausen Joerg , Jacoby Edgar , Lang Marc , Gabriel Tobias , Hofmann Francesco , Kallen Joerg , Jeay Sébastien , Gessier Francois
Published: May 2015

The antiproliferative transcriptional activity of the p53 tumor suppressor is inhibited by the binding of its transactivation domain to the regulator protein Mdm2. Overexpression of Mdm2 or amplification of its gene, leading to a loss of p53 function, has been observed in various tumors. An attractive approach to restore p53 activity in such tumors and to inhibit their growth is to prevent the association of the two proteins by blocking the p53 binding pocket of Mdm2 with a small molecule. In this presentation, we report how the starting point of CGM097 was discovered and how innovative medicinal chemistry efforts led to further optimization of the potency and physico-chemical properties, resulting in CGM097, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction.

Citation Format: Keiichi Masuya, Pascal Furet, Stefan Stutz, Philipp Holzer, Carole Pissot-Soldmann, Nicole Buschmann, Thérèse Valat, Stéphane Ferretti, Stephan Ruetz, Caroline Rynn, Joerg Berghausen, Edgar Jacoby, Marc Lang, Tobias Gabriel, Francesco Hofmann, Joerg Kallen, Sébastien Jeay, Francois Gessier. Discovery of CGM097 as a novel Mdm2 inhibitor. [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 DDT01-01. doi:10.1158/1538-7445.AM2014-DDT01-01
Abstract LB-10: Rational design of small molecules targeting the Ras GEF, SOS1
Authors: Evelyn Chris , Duan Xin , Biesiada Jacek , Seibel William , Meller Jaroslaw , Zheng Yi
Published: May 2015

Ras GTPases regulate multiple intracellular signaling processes involved in gene expression, cell proliferation, and cell survival. Driver mutations of Ras signaling components including K,N,H-Ras, EGFR, PDGFR, Raf, PI3K, and Akt have been found in many types of human cancers. The activation of Ras is catalyzed by guanine-nucleotide exchange factors (GEFs), which stimulate the exchange of GDP for GTP. SOS1 is a major RasGEF that transduces receptor tyrosine kinase signals to Ras and associated ERK/Akt pathways. SOS1 gain-of-function mutations have been found in Noonan syndrome patients. In addition, SOS1 has been shown to be differentially expressed in prostate and breast cancer cells, and is involved in malignancies dependent upon aberrant Ras signaling. In the current studies, we undertake a structure-based virtual screening approach, coupled with biochemical and cell biological validations, to identify lead chemical inhibitors targeting the Ras catalytic domain of SOS1. From a 118,500 compound subset of the NCI/DTP Open Chemical Repository, 135 showed optimal docking energy to a grid of the SOS1 catalytic site from which 36 were selected for experimental screening by a guanine nucleotide exchange assay, i.e. FL-GDP dissociation of Ras under the catalysis of SOS1. Two compounds were confirmed as true hits (NSC-674954 and NSC-658497), of which NSC-658497 displayed micromolar IC50s in both inhibiting FL-GDP dissociation (IC50 - 22.2 µM) from Ras and TR-GTP loading (IC50 - 40.8 µM) of Ras catalyzed by Sos1. In addition, NSC-658497 displayed a target binding Kd of ∼7.0 µM as assayed by microscale thermophoresis, along with dose-dependently disrupting the SOS1 interaction with Ras as assayed by a GST-Ras pull-down analysis. Mutagenesis studies mapped NSC-658497 action site to the catalytic site in SOS1, involving specifically residues I825, T828, T829, and Y912. SAR analysis revealed that NSC-658497 elicits its inhibitory effect on SOS1 through a benzopyran and nitrophenyl moiety. In fibroblast cells, NSC-658497 showed dose-dependent efficacy in inhibiting EGF-stimulated Ras and ERK/AKT activities. Furthermore, NSC-658497 dose-dependently inhibited NIH/3T3, MEF, and MIA-PaCa-2 pancreatic cancer cell proliferation in conjunction with their respective downstream Ras-dependent ERK/AKT activities. Thus, we have identified a class of lead chemical inhibitors targeting SOS1 that can serve as useful tools for studying SOS1 mediated oncogenesis and as hits for further development of future cancer therapeutics.

Citation Format: Chris Evelyn, Xin Duan, Jacek Biesiada, William Seibel, Jaroslaw Meller, Yi Zheng. Rational design of small molecules targeting the Ras GEF, SOS1. [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-10. doi:10.1158/1538-7445.AM2014-LB-10
Abstract LB-107: Inhibiting TNKS sensitizes KRAS mutant cancer cells to MEK inhibitors by suppressing FGFR2 feedback signaling
Authors: Shao Wenlin , Schoumacher Marie , Hurov Kristen , Lehar Joseph , Yan-Neale Yan , Mishina Yuji , Sonkin Dmitriy , Korn Joshua , Flemming Daisy , Jones Michael , Antonakos Brandon , Cooke Vessilina , Stump Mark , Danial Nika , Sellers William
Published: May 2015

Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis and mitosis, and are therefore considered as attractive targets for anti-cancer treatment. Using unbiased combination screens in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors in KRAS mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and anti-tumor activity both in vitro and in vivo than effects observed by previously reported MEK inhibitor combinations. Altogether, our data provides a strong rationale for combined targeting of TNKS and MEK in KRAS mutant cancers.

Citation Format: Wenlin Shao, Marie Schoumacher, Kristen Hurov, Joseph Lehar, Yan Yan-Neale, Yuji Mishina, Dmitriy Sonkin, Joshua Korn, Daisy Flemming, Michael Jones, Brandon Antonakos, Vessilina Cooke, Mark Stump, Nika Danial, William Sellers. Inhibiting TNKS sensitizes KRAS mutant cancer cells to MEK inhibitors by suppressing FGFR2 feedback signaling. [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-107. doi:10.1158/1538-7445.AM2014-LB-107
Abstract LB-109: Therapeutic targeting of Heat shock factor 1 in chronic lymphocytic leukemia
Authors: Rao Rekha M. , Abdulraheem Yacoub , Kambhampati Suman , Ganguly Siddhartha
Published: May 2015

Heat shock factor 1 (HSF1) is a stress-activated transcription factor, that up-regulates the transcription of heat shock proteins (Hsps) and a growing list of tumor-promoting genes. HSF1-induced genes promote protein folding and maturation (through Hsps and associated co-chaperones) as well as orchestrate the transcription of tumor-promoting genes (for e.g., VEFGR, HIF1-alpha, GLUT-1, etc). In this study we propose to evaluate the efficacy of inhibiting HSF1 in Chronic Lymphocytic Leukemia (CLL), a disease that invariably relapses after patients show complete or partial response to first line chemotherapy. Consistent with the established tumor-promoting roles of HSF1, we report that CD19+ B cells isolated from relapsed/refractory CLL patients show high levels of immunofluorescent, nuclear HSF1 staining compared to normal CD19+ B cells, where it is weakly expressed and pre-dominantly cytosolic. CD19+ B primary CLL cells also show enhanced expression of HSF1 as assessed by immunoblot analysis compared to normal CD19+ cells. Treatment of cultured and primary CLL CD19+ B cells with the HSF1 inhibitor triptolide causes a dose-dependent increase in apoptosis, while relatively sparing normal CD19+ B cells. Treatment with triptolide results in the reduced expression of Hsp40, Hsp70 and Hsp27 proteins and a concomitant increase in the PARP cleavage and Caspase 3 cleavage in cultured and primary CLL cells. Lentiviral shRNA-mediated knockdown of HSF1 or triptolide treatment decreased the levels of Bcl-XL and pro-survival signaling molecules, phosphorylated STAT3 (Y-705) and AKT (S473). Based on the established role of Hsps in cytoprotection and resistance to chemotherapy, we hypothesized that inhibition of HSF1 would sensitize CLL cells to agents that promote the accumulation of misfolded proteins (for e.g. Hsp90 inhibitors) or inhibit their disposal (for e.g. treatment with autophagy inhibitors) by inducing proteotoxicity. Consistent with this hypothesis, knockdown of HSF1 or co-treatment with triptolide and the autophagy inhibitor chloroquine resulted in superior anti-CLL activity compared to treatment with either agent alone. Similarly, knockdown of HSF1 or its inhibition with triptolide also sensitized CLL cells to the Hsp90 inhibitor, 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). These pre-clinical studies provide a strong rationale to test the in vitro and in vivo activity of HSF1 inhibitors in combination with agents that promote proteotoxic stress against CLL.

Citation Format: Rekha M. Rao, Yacoub Abdulraheem, Suman Kambhampati, Siddhartha Ganguly. Therapeutic targeting of Heat shock factor 1 in chronic lymphocytic leukemia. [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-109. doi:10.1158/1538-7445.AM2014-LB-109
Abstract LB-132: The central role of EED in orchestration of polycomb group complexes
Authors: Cao Qi , Wang Xiaoju , Zhao Meng , Yang Rendong , Malik Rohit , Qiao Yuanyuan , Poliakov Anton , Cao Xuhong , Harris Clair , Feng Felix Y. , Kalantry Sundeep , Qin Zhaohui , Dhanasekaran Saravana M. , Chinnaiyan Arul M.
Published: May 2015

Polycomb Group (PcG) proteins play a vital role in establishing and maintaining gene expression patterns during cellular differentiation and development. They are epigenetic regulators that are responsible for the repression of target genes involved in development and cell fate specification. PcG proteins function as multimeric, chromatin-associated protein complexes. In mammals, there are two major Polycomb Repressive Complexes, PRC1 and PRC2 that possess histone-modifying activity crucial for their role in gene repression through methylation of histone H3K27, as well as the mono-ubiquitination of histone H2AK119. Components of both PRC1 and PRC2 have been shown to be elevated in a number of tumor types and play an important role in neoplastic progression.

Major components of human PRC2 include the histone methyltransferase, Enhancer of Zeste Homolog 2, and its known binding partners, Embryonic Ectoderm Development (EED) and Suppressor of Zeste 12 (SUZ12) that collectively function as a multi-subunit complex trimethylating histone H3K27. Fundamental collaborators of PRC2 in epigenetic silencing include human PRC1 which consists of B lymphoma Mo-MLV insertion region 1 (BMI1), RING1A (also known as RING1), and RING1B (also known as RING2 or RNF2). Together, they function as a multi-protein complex to ubiquitinate histone H2A at lysine 119 (uH2A). The leading hypothesis regarding PRC2 and PRC1 interaction is that PRC2-mediated tri-methylation of H3K27 recruits PRC1 to genomic loci leading to chromatin condensation and epigenetic silencing of target genes. While the evidence linking PRC1 and PRC2 is circumstantial, a physical or molecular link between these complexes has not been established. In this study, we make an unexpected observation that EED, previously considered a critical component of PRC2, is instead a shared component of PRC2 and PRC1 that functions to interchange these epigenetic complexes at sites of histone modification. This observation markedly enhances our understanding of how PRC2 and PRC1 coordinate epigenetic regulation and may have implications in therapeutically targeting these master regulators of transcription.

Citation Format: Qi Cao, Xiaoju Wang, Meng Zhao, Rendong Yang, Rohit Malik, Yuanyuan Qiao, Anton Poliakov, Xuhong Cao, Clair Harris, Felix Y. Feng, Sundeep Kalantry, Zhaohui Qin, Saravana M. Dhanasekaran, Arul M. Chinnaiyan. The central role of EED in orchestration of polycomb group complexes. [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-132. doi:10.1158/1538-7445.AM2014-LB-132
Abstract LB-138: Autophagy regulator BECN1 acts as a context-dependent tumor suppressor opposing parity-associated and WNT1-driven mammary tumorigenesis
Authors: Cicchini Michelle , Chakrabarti Rumela , Kongara Sameera , Price Sandy , Nahar Ritu , Lozy Fred , Zhong Hua , Vazquez Alexei , Kang Yibin , Karantza Vassiliki
Published: May 2015

Earlier studies reported allelic deletion of the essential autophagy regulator BECN1 in breast cancers implicating BECN1 loss and defective autophagy in tumorigenesis. Recent studies questioned the tumor suppressive role of autophagy, as Atg defects, including Becn1 deletion, suppress tumorigenesis in mouse tumor models. For the first time, we report that monoallelic Becn1 loss has a context-specific tumor-promoting function in parity-associated and WNT-driven mammary tumorigenesis. Our studies demonstrate that Becn1 heterozygocity promotes immature mammary epithelial cell expansion, Receptor Activator of NFκB (RANK) signaling and mammary tumorigenesis in cooperation with the progenitor cell-transforming WNT pathway. Similar to our mouse model, low BECN1 expression and WNT pathway activation in human breast tumors correlate with triple negative breast cancers (TNBCs), RANK axis activation and poor prognosis. Our results provide novel insight in the seemingly paradoxical role of BECN1 in tumorigenesis and the basis for further studies on pathophysiology and treatment of clinically aggressive TNBCs.

Citation Format: Michelle Cicchini, Rumela Chakrabarti, Sameera Kongara, Sandy Price, Ritu Nahar, Fred Lozy, Hua Zhong, Alexei Vazquez, Yibin Kang, Vassiliki Karantza. Autophagy regulator BECN1 acts as a context-dependent tumor suppressor opposing parity-associated and WNT1-driven mammary tumorigenesis. [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-138. doi:10.1158/1538-7445.AM2014-LB-138
Abstract LB-142: Selective inhibition of BET bromodomains epigenetic signaling interferes with the bone-associated tumor vicious cycle
Authors: Lamoureux Francois , Baud'Huin Marc , Calleja Lidia Rodriguez , Jacques Camille , Redini Francoise , Bradner James E. , Heymann Dominique , Ory Benjamin
Published: May 2015

Selective BET bromodomains epigenetic signaling inhibition as a therapeutic strategy in primary bone tumors

The vicious cycle established between bone associated tumors and bone resorption is the central problem with therapeutic strategies against primary bone tumors and bone metastasis. The bromodomain and extra-terminal domain (BET) protein family is an important class of “histone reading protein” capable to recognize the N-acetylation of lysine residues on histone tails. BET bromain proteins have recently been described as regulators of MYC expression in various tumors. In this study, we report data to support inhibition of BET bromodomain as a novel and promising therapeutic strategy that target simultaneously the three partners of the vicious cycle. Treatment with JQ1, a unique BET bromodomain inhibitor, reduced cell viability and induced apoptosis in osteosarcoma cells and, inhibited osteoblastic differentiation in vitro. In vivo, BET inhibitor (IP; 50mg/kg) significantly inhibits tumor growth by 70% and prolongs survival in both POS-1 syngenic and MMNG/HOS xenograft models compared to control. Additionally, these results were accompanied by a decrease of associated bone lesions.

These effects were associated with transcriptional silencing of MYC and RUNX2, resulting from the depletion of BRD4 from their respective loci. Moreover, JQ1 also inhibited osteoclast differentiation by interfering with BRD4-dependent RANKL activation of NFATC1 transcription. Collectively, our data indicates that JQ1 is a potent inhibitor of osteoblast and osteoclast differentiation as well as bone tumor development.

Citation Format: Francois Lamoureux, Marc Baud'Huin, Lidia Rodriguez Calleja, Camille Jacques, Francoise Redini, James E. Bradner, Dominique Heymann, Benjamin Ory. Selective inhibition of BET bromodomains epigenetic signaling interferes with the bone-associated tumor vicious cycle. [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-142. doi:10.1158/1538-7445.AM2014-LB-142