tbuckley/cabot-search huggingface dataset:
A phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in metastatic colorectal cancer.
Authors: Antoine Hollebecque, Guillem Argiles, Thierry Andre, Andres Cervantes, Catherine Leger, Aude Valette, Nadia Amellal, Ronan Fougeray, Josep Tabernero
Journal: Journal of Clinical Oncology (2017)

TPS3626 Background: Trifluridine/tipiracil, also known as TAS‐102, is a combination of an antineoplastic thymidine‐based nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride). The antitumor activity of combined trifluridine/tipiracil and oxaliplatin has been studied in gastrointestinal tumor xenografts, including a 5‐FU resistant subline, using a nude mouse model. This study demonstrated increased antitumor activity for the combination compared to trifluridine/tipiracil or oxaliplatin alone (p &lt; 0.001) (Nukatsuka et al., Anticancer Res 2015). These data support the rationale for clinical use of the combination. We describe a phase 1, international, dose-escalation study of the combination in metastatic colorectal cancer (mCRC). Methods: This trial includes mCRC patients pretreated with at least one line of standard chemotherapy. The 14‐day administration schedule of trifluridine/tipiracil differs from current clinical practice to avoid overlapping toxicity, notably decreased neutrophils due to oxaliplatin or trifluridine/tipiracil. Trifluridine/tipiracil is administered orally (cohort 1: 25 mg/m² bid; cohort 2: 30 mg/m² bid; cohort 3: 35 mg/m² bid) from day 1 to 5; and oxaliplatin at 85 mg/m² (with a possibility to reduce to 65 mg/m²) on day 1. The primary objective is to determine the maximum tolerated dose (MTD) through a 3+3 design. Secondary objectives include safety, pharmacokinetics, and preliminary efficacy (overall survival, progression‐free survival, overall response rate and biomarkers). As of December 2016, no dose‐limiting toxicities had been reported in cohorts 1 or 2. The MTD has not yet been reached and dose‐escalation continues with enrollment in cohort 3 at full dose for both drugs (trifluridine/tipiracil 35 mg/m² bid and oxaliplatin 85 mg/m²). Once established, the MTD will be confirmed in 6 additional patients to define the recommended dose to be used in the expansion part of the study planned in the same patient population. The results of the dose‐escalation part are expected in 2017. (NCT02848443). Clinical trial information: NCT02848443.
Abstract 1676: EZH2 inhibitors in immunotherapy of melanoma
Authors: Peter Hersey, Stuart Gallagher, Jessamy Tiffen, Elena Shklovskaya, Stephen Wilson, Fabian Filipp
Journal: Cancer Research (2017)

Abstract EZH2 contains the catalytic subunit of the PRC2 complex, which plays a role in maintenance of stem cell- like state of cancer cells and in the progression of melanoma. Our previous studies have shown that hyperactivation of EZH2 by somatic mutations or copy number gain occurs in 20% of melanoma patients and impacts overall survival. Elevated activity of EZH2 in cancer can be targeted by small molecule drugs (e.g. GSK126) and is associated with sensitivity to apoptotic cell death. Transcriptomic profiling showed that several well-known tumor suppressors such as BOK, NDRG1 and RASSF5 are down-regulated in cells with abnormalities in EZH2, which can be reversed by inhibitor treatment. By using our in vitro EZH2 drug targeting assay we validated genes associated with immune recognition and MHC class II antigen presentation such as HLA A and B,DR and CD74 (HLA DR invariant chain). In addition, ChIP-Seq studies identified adhesion molecules, chemokine ligands, and receptors involved in traffic of lymphocytes to tumors as well as the function of NK cells. Treatment of melanoma with EZH2 inhibitors showed increased killing by NK cells suggesting that an immunosuppressive effect of EZH2 involving both innate and adaptive immunity. In a mouse model of subcutaneous B16 melanoma, a course of daily treatment with an EZH2 inhibitor did not change tumour growth or immune responses in immunosufficient mice but caused a transient 9-fold increase in circulating Ly6G+ [granulocytic] myeloid-derived suppressor cells [MDSCs] suggesting the effect of EZH2 modifiers on the myeloid compartment. In summary, patients with somatic activation of EZH2 may benefit from treatment combinations that include inhibitors of EZH2. Supported by NHMRC program grant 633004, Sydney medical school foundation and Cancer Institute NSW. F.V.F. is grateful for the support of grants CA154887 from the National Institutes of Health, National Cancer Institute and CRCC CRN-17-427258. Citation Format: Peter Hersey, Stuart Gallagher, Jessamy Tiffen, Elena Shklovskaya, Stephen Wilson, Fabian Filipp. EZH2 inhibitors in immunotherapy of melanoma [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 1676. doi:10.1158/1538-7445.AM2017-1676
A phase II study (KSCC/HGCSG/CCOG/PerSeUS1501B) of trastuzumab plus S-1 and oxaliplatin for HER2-positive advanced gastric cancer.
Authors: Katsunori Shinozaki, Satoshi Yuki, Tomomi Kashiwada, Tetsuya Kusumoto, Masaaki Iwatsuki, Hironaga Satake, Kazuma Kobayashi, Taito Esaki, Yuichiro Nakashima, Nobuhide Kubo, Shoji Tokunaga, Takayuki Shimose, Akitaka Makiyama, Hiroshi Saeki, Eiji Oki, Hideo Baba, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2017)

4059 Background: A combination of S-1 and cisplatin (SP) has been the standard regimen for advanced gastric cancer (AGC) in East Asia. The combination of S-1 and oxaliplatin (SOX100) was demonstrated to be non-inferior to SP in the randomized phase III study. The ToGA study demonstrated that trastuzumab (T-mab) combination therapies with cisplatin and fluoropyrimidines improved the overall survival of patients with HER2-positive AGC. This multicenter study is the first phase II trial to assess the efficacy and safety of T-mab in combination with S-1 and oxaliplatin (HER-SOX130) in HER2-positive AGC. Methods: Patients with HER2-positive AGC or recurrent gastric cancer defined to be IHC 3+ or IHC 2+/FISH positive received 80 mg/m 2 S-1 per day orally on days 1–14, 130 mg/m 2 oxaliplatin intravenously on day 1, and T-mab (8-mg/kg loading dose and 6 mg/kg thereafter) intravenously on day 1 of a 21-day cycle until one of the criteria for withdrawal of the study treatment occurred. The primary end-point was the response rate (RR). Adverse events were recorded based on the NCI-CTCAE Vers.4.0. The threshold response rate was defined as 50%, and the expected rate was set at 70%, with an 80% power and a 1-sided alpha value of 0.05. The calculated sample size was 37 patients. Results: For this study, 42 patients (median age, 66 years) were enrolled from June 2015 to May 2016. Three patients were excluded owing to ineligibility. Efficacy and safety analyses were conducted in the full analysis set of 39 patients. The proportion of patients with IHC 3+ was 87%. The confirmed RR assessed by the independent review committee was 82.1(32/39) % (95% confidence interval [CI]: 67.3–91.0), and the disease control rate was 87.2(34/39) % (95% CI: 73.3–94.4). The incidence rates of grade 3 or 4 adverse events were as follows: neutropenia, 12.8%; thrombocytopenia, 17.9%; anemia, 10.3%; sensory neuropathy, 5.1%; anorexia, 17.9%; diarrhea, 7.7%; and teary eyes, 2.6%. Conclusions: HER-SOX130 demonstrated encouraging efficacy with a favorable safety profile. The survival benefit of this regimen needs to be validated by conducting further follow-up of patients. Clinical trial information: 000017552.
Abstract 524: Characterizing the <i>in vitro</i> and <i>in vivo</i> effects of the PIM kinase inhibitor HS140 in triple-negative human breast cancer
Authors: Michael Cobb, Lucas Hunter, David Carlson, David Darr, Timothy Haystead, Antonio T. Baines
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancer (TNBC) lacks expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, making it the worse subtype of all breast cancers. Currently, there are no molecular targeted therapies for this cancer and chemotherapy is only successful in a limited number of patients. Recent studies suggest that members of the oncogenic PIM kinase family, especially PIM-1, play a significant role in the growth of TNBC. However, there is very limited information on the role other PIM family members have in the growth and development of TNBCs. As an attempt to address this concern, we treated a panel of TNBC cell lines with HS140, a PIM-2 kinase inhibitor developed in the laboratory. Using cytotoxicity assays, we were able to demonstrate a decrease in anchorage-dependent growth of cell lines at different concentrations of HS140. Also, a triple negative breast cancer GEMM (C3TAg) was used for an efficacy study. Mice (FVB/N background) have C(3)SV40 T-antigen resulting in inactivation of p53 and Rb. Nine mice received HS140 treatment (80mg/kg BIW IP) and 14 left untreated for control (non-treatment [NT]). All mice were monitored for weight loss and timespan to tumor development 5 times weekly. Tumor volumes at 21 days were significantly (Mann-Whitney, p=0.0002) reduced in the treated cohort with a mean of 109mm3 (range of 0-5000) compared to untreated 1393mm3 (0-239). We observed no toxicities with body mass stable at the treatment dose of 80mg/kg. Additionally, three mice from untreated and three mice from treated cohorts were chosen for blood sampling pre- and post-treatment via a submandibular bleed; no significant differences were noted in WBC, RBC, PLT, or HGB between untreated and treated cohorts. Overall, these results suggest that other members of the PIM kinase family, including PIM-2, have an important function in the growth and development of TNBC and may serve as a potential molecular target for future therapeutics. Citation Format: Michael Cobb, Lucas Hunter, David Carlson, David Darr, Timothy Haystead, Antonio T. Baines. Characterizing the in vitro and in vivo effects of the PIM kinase inhibitor HS140 in triple-negative human breast cancer [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 524. doi:10.1158/1538-7445.AM2017-524
L‐ornithine L‐aspartate in bouts of overt hepatic encephalopathy
Authors: Sandeep Singh Sidhu, Barjesh Chander Sharma, Omesh Goyal, Harsh Kishore, Navpreet Kaur
Journal: Hepatology (2017)

High-quality data on the efficacy of L-ornithine L-aspartate (LOLA) in patients with cirrhosis and bouts of overt hepatic encephalopathy (OHE) are missing. We evaluated the efficacy of intravenous LOLA in the reversal of bouts of OHE in patients with cirrhosis. In this prospective, double-blind, randomized, placebo-controlled trial conducted at two tertiary care institutes in India, 370 patients with cirrhosis and bouts of OHE were screened. After exclusion, 193 (52.16%) patients were randomized to receive either intravenous infusions of LOLA (n = 98), 30 g daily, or placebo (n = 95) for 5 days. Standard of care treatment (including lactulose and ceftriaxone) was given in both groups. Randomization was done centrally (http://www.sealedenvelope.com/). All study personnel were blinded to the treatment assignment. Fasting venous ammonia levels were estimated daily from 0 to 5 days. Serum tumor necrosis factor-alpha, interleukins, hemogram, and liver and renal function tests were performed at days 0 and 5. Primary outcome was mental state grade at day 5 of treatment. The grade of OHE was significantly lower in the LOLA group (compared to placebo) on days 1-4 but not on day 5. The mean time taken for recovery was lower in the LOLA group compared to the placebo group (1.92 ± 0.93 versus 2.50 ± 1.03 days, P = 0.002; 95% confidence interval -0.852 to -0.202). Venous ammonia at day 5 and length of hospital stay were significantly lower in the LOLA group. No significant difference in interleukins was seen between the groups. Conclusion: In patients with bouts of OHE, intravenous LOLA (as an add-on therapy to lactulose and ceftriaxone) significantly improves the grade of OHE over days 1-4, but not on day 5, and decreases venous ammonia, time of recovery, and length of hospital stay. (Hepatology 2018;67:700-710).
Abstract 1644: Combination of MT-3724 with sirolimus reduces anti-drug antibody response and prolongs drug exposure
Authors: Jack P. Higgins, Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jensing Liu, Erin K. Willert
Journal: Cancer Research (2017)

Abstract Molecular Templates is developing engineered toxin bodies (ETBs), potent recombinant immunotoxins that combine the specificity of an antibody fragment with the powerful direct cytotoxicity of the Shiga-like toxin A subunit. ETBs can induce their own internalization, route through the cell in a predictable manner, enzymatically and irreversibly destroy ribosomes to shutdown protein synthesis and induce apoptosis of tumor cells. This mechanism of action is distinct from that of other therapeutics, making ETBs an attractive treatment for patients who have become resistant to chemotherapy and other treatment modalities. MT-3724 is Molecular Templates’ first-generation ETB targeting CD20, a surface receptor that is highly expressed on malignant B cells in hematological malignancies. Pre-clinical and clinical studies have shown promising results for non-Hodgkin’s lymphoma cell lines and patients; however anti-drug antibodies are formed in experimental animals and patients after repeat dosing. Sirolimus (rapamycin) is a macrolide compound approved to prevent organ rejection and in LAM, and has been used in tolerization protocols with replacement enzymes. In pre-clinical studies, we have co-administered sirolimus in combination with MT-3724 in rodents as well as in a non-human primate model in order to reduce the anti-drug antibody response to MT-3724. These studies demonstrated that the combination of sirolimus with MT-3724 decreased anti-drug antibody response, prolonged serum exposure of MT-3724, and improved B-cell depletion as compared to MT-3724 alone. Molecular Template’s ETB technology has resulted in potent and targeted therapeutic agents that have a unique mechanism of action in the field of oncology. Our first-generation, CD20-targeted therapeutic, MT-3724, has promising clinical results in the refractory setting for non-Hodgkin’s lymphoma. The combination of sirolimus with MT-3724 is an attractive and feasible regimen which will be further explored in clinical studies. Citation Format: Jack P. Higgins, Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jensing Liu, Erin K. Willert. Combination of MT-3724 with sirolimus reduces anti-drug antibody response and prolongs drug exposure [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 1644. doi:10.1158/1538-7445.AM2017-1644
A Call for Social Responsibility and Suicide Risk Screening, Prevention, and Early Intervention Following the Release of the Netflix Series <i>13 Reasons Why</i>
Authors: Kimberly H. McManama O'Brien, John R. Knight, Sion K. Harris
Journal: JAMA Internal Medicine (2017)

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Abstract 3338: A role for FGFR4 in growth and survival of Ewing sarcoma cells
Authors: Justin J. Montoya, Daniel H. Wai, David W. Lee, Peter A. Azorsa, Oliver B. Pepper, Robert J. Arceci, David O. Azorsa
Journal: Cancer Research (2017)

Abstract Ewing sarcoma is the second most common cancer of bone and soft tissue arising in children and young adults. Although the survival rate has improved for patients treated for localized disease, the survival rate for patients with metastatic tumor remains lower than 30%. In order to identify novel therapeutic targets and to better understand the genes involved in growth and survival of Ewing sarcoma, we employed a functional genomics approach based on siRNA screening. Four Ewing sarcoma cell lines, TC-32, TC-71, SK-ES-1 and RD-ES, were transfected with a library of siRNA targeting 287 cancer-associated genes. The resulting siRNA screening data for each cell line were normalized and statistical cut-offs were determined. The results indicated that siRNAs targeting Fibroblast Growth Factor Receptor 4, FGFR4 were among the most effective in reducing cell viability in all four of the Ewing sarcoma cell lines. Validation of the siRNA screens showed that siRNAs to FGFR4, reduced viability much greater that those to FGFR1, FGFR2, or FGFR3. Furthermore, siRNA targeting FGFR4 were able to induce caspase 3 activity. FGFR4 protein is expressed on Ewing sarcoma cells as determined by western blot analysis, although expression levels were lower compared to FGFR4 expression on rhabdomyosarcoma cells. Targeting FGFR activity in Ewing sarcoma cells using a pan-FGFR inhibitors PD-173074 and BGJ-398 demonstrated that Ewing sarcoma cells were sensitive to FGFR inhibition. Furthermore, treatment of Ewing sarcoma cells with the selective FGFR4 inhibitor BLU9931 resulted in growth inhibition and decreased ERK signaling. These results indicate that FGFR4 may play an important role in growth and survival of Ewing sarcoma and could serve as a potential therapeutic target for this disease. Citation Format: Justin J. Montoya, Daniel H. Wai, David W. Lee, Peter A. Azorsa, Oliver B. Pepper, Robert J. Arceci, David O. Azorsa. A role for FGFR4 in growth and survival of Ewing sarcoma cells [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 3338. doi:10.1158/1538-7445.AM2017-3338
Tumor-Treating Fields: A Fourth Modality in Cancer Treatment
Authors: Elijah J. Mun, Hani M. Babiker, Uri Weinberg, Eilon D. Kirson, Daniel D. Von Hoff
Journal: Clinical Cancer Research (2017)

Abstract Despite major advances in therapy, cancer continues to be a leading cause of mortality. In addition, toxicities of traditional therapies pose a significant challenge to tolerability and adherence. TTFields, a noninvasive anticancer treatment modality, utilizes alternating electric fields at specific frequencies and intensities to selectively disrupt mitosis in cancerous cells. TTFields target proteins crucial to the cell cycle, leading to mitotic arrest and apoptosis. TTFields also facilitate an antitumor immune response. Clinical trials of TTFields have proven safe and efficacious in patients with glioblastoma multiforme (GBM), and are FDA approved for use in newly diagnosed and recurrent GBM. Trials in other localized solid tumors are ongoing. Clin Cancer Res; 24(2); 266–75. ©2017 AACR.
Abstract 1068: Driver pathway blockage synergizes with PLK1 inhibition in anaplastic thyroid cancer
Authors: Daniela De Martino, Emrullah Yilmaz, Arturo Orlacchio, Antonio Di Cristofano
Journal: Cancer Research (2017)

Abstract Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies, with a median survival of less than 6 months from the time of diagnosis. Molecular changes that characterize ATC have been recently well defined and involve most often p53 mutations, and activation of PI3K, RAS and BRAF. PLK1, an essential mitotic regulator, has been found overexpressed in ATC. Previous data from our lab have shown that PLK1 inhibitors are effective in ATC cell lines. However PLK1 inhibition often results in escape from growth arrest through mitotic slippage. This leads to the generation of polyploid, genetically unstable, cell populations. We have tested the effect of combining PLK1 and PI3K inhibitors in ATC cell lines. Combined treatment with the PLK1 inhibitor BI6727 and the PI3K inhibitor BKM120 resulted in a significant synergistic effect in ATC cell lines with high levels of AKT activity, but not in those with undetectable pAKT. Combination of the two drugs enhanced the G2/M arrest at doses in which the single drugs showed no effect. In addition, it led to a massive reduction of the tetraploid cells population. Furthermore, combined treatment with BI6727 and BKM120 in PI3Khigh cell lines showed a significant induction of apoptosis in a time- and dose-dependent manner. Combined inhibition of PI3K and PLK1 was extremely effective in inhibiting tumor growth in vivo, in an immunocompetent allograft model of ATC. Our results show that combination of PLK1 and PI3K inhibitors is an effective treatment for ATC cells with high levels of PI3K signaling. This combination results in cell cycle arrest, inhibition of of tetraploid cell generation, and induction of apoptosis, suggesting a clear therapeutic potential. Citation Format: Daniela De Martino, Emrullah Yilmaz, Arturo Orlacchio, Antonio Di Cristofano. Driver pathway blockage synergizes with PLK1 inhibition in anaplastic thyroid cancer [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 1068. doi:10.1158/1538-7445.AM2017-1068