bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1220: A novel PTK7-targeted antibody-drug conjugate eliminates tumor-initiating cells and induces sustained tumor regressions
Authors: Damelin Marc Isaac , Bankovich Alex , Bernstein Jeff , Lucas Justin , Chen Liang , Williams Sam , Park Albert , Aguilar Jorge , Ernstoff Elana , Charati Manoj , Dushin Russell , Jackson-Fisher Amy , Aujay Monette , Lee Christina , Ramoth Hanna , Milton Milly , Hampl Johannes , Lazetic Sasha , Pulito Virginia , Armellino Douglas , Rosfjord Edward , Guffroy Magali , Falahatpisheh Hadi , King Lindsay , Barletta Frank , Stull Robert , Pysz Marybeth , Escarpe Paul , Liu David , Foord Orit , Gibson Brenda , Powell Eric , O’Donnell Christopher , Xin Xiaohua , Gerber Hans Peter , Sapra Puja , Dylla Scott 
Published: July 2016

Abstract
Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer and non-small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor regrowth and metastasis. Here we identify Protein Tyrosine Kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase, as an antigen that is enriched on TICs in low-passage patient-derived xenografts (PDX) of TNBC, NSCLC and other tumor types. An anti-PTK7 antibody-drug conjugate (ADC) was generated from a humanized anti-PTK7 monoclonal antibody, a cleavable valine-citrulline-based linker and the Aur0101 auristatin microtubule inhibitor. The anti-PTK7 ADC induced sustained regressions of TNBC, NSCLC and ovarian cancer PDX, with improved activity over standard-of-care chemotherapy, and reduced the frequency of TICs as determined by serial transplantation experiments. Moreover, the ADC may have additional mechanisms of action, including an anti-angiogenic effect, that promote anti-tumor immune responses. Together these preclinical results indicate the potential of the anti-PTK7 ADC to improve the long-term survival of cancer patients. The ADC is currently being tested in a Phase 1 clinical trial, from which interim results will be presented.
Citation Format: Marc Isaac Damelin, Alex Bankovich, Jeff Bernstein, Justin Lucas, Liang Chen, Sam Williams, Albert Park, Jorge Aguilar, Elana Ernstoff, Manoj Charati, Russell Dushin, Amy Jackson-Fisher, Monette Aujay, Christina Lee, Hanna Ramoth, Milly Milton, Johannes Hampl, Sasha Lazetic, Virginia Pulito, Douglas Armellino, Edward Rosfjord, Magali Guffroy, Hadi Falahatpisheh, Lindsay King, Frank Barletta, Robert Stull, Marybeth Pysz, Paul Escarpe, David Liu, Orit Foord, Brenda Gibson, Eric Powell, Christopher O’Donnell, Xiaohua Xin, Hans Peter Gerber, Puja Sapra, Scott Dylla. A novel PTK7-targeted antibody-drug conjugate eliminates tumor-initiating cells and induces sustained tumor regressions. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1220.
Abstract 123: Multiplatform molecular profiling of invasive lobular breast cancer
Authors: Nunes Raquel A. , Arguello David , Gatalica Zoran , Reddy Sandeep , Swain Sandra M. 
Published: July 2016

Abstract
Introduction: Invasive lobular breast cancer (ILC) is the second most common subtype of invasive breast cancer accounting for 10% of breast cancer diagnosis. ILC has particular histological and clinical characteristics and a distinct response to therapy. Characterizing the molecular alterations in ILC may lead to an improved understanding of its biology and provide new therapeutic options. The purpose of this study is to describe the molecular profile of ILC and compare it to the one of invasive ductal cancer (IDC).
Methods: Three-hundred and thirty nine pure ILC specimens profiled from January 2012 - November 2015 were evaluated (Caris Life Sciences, Phoenix, AZ). Multiplatform profiling consisted of gene sequencing (next generation sequencing [NGS]), gene amplification (CISH or FISH), and protein expression (immunohistochemistry [IHC]). Molecular characteristics of estrogen receptor (ER) positive and human epidermal growth receptor factor 2 (HER2) negative pure ILC (n = 236) and IDC (n = 286) were compared.
Results: By IHC, ER expression was present in 87.7% (277/316), progesterone receptor in 59.6% (198/313), HER2 in 3.5% (11/313), androgen receptor in 87% (262/301), PD-L1 in 8.1% (12/148) and PTEN in 63.3% (198/313). Amplifications were detected in MYC (7.7%, 2/26), EGFR (8.3%, 2/24), ERBB2 (4.5%, 13/290) and TOP2A (1.3%, 3/236). Mutations were detected in AKT1 (4.7%, 9/191), ATM (3.7%, 7/190), BRCA1 (4.2%, 4/96), BRCA2 (9.5%, 9/95), ERBB2 (7.5%, 14/186), PIK3CA (54.5%, 103/189), PTEN (7.9%, 15/189), and TP53 (13.4%, 25/186). A comparison of ER-positive/HER2-negative invasive lobular and ductal carcinomas revealed significant differences in AR expression (89.7% vs 79.6%, p = 0.0022), and mutations in CDH1 (10.1% vs 0.0%, p = 0.0001), ERBB2 (8.2% vs 2.1%, p = 0.0079), and TP53 (10.3% vs 31.8%, 0.0001).
Conclusions: Multiplatform testing of this large series of ILC reveals recurrent alterations and a distinct molecular profile when compared to IDC. These support the definition of ILC as biologically distinct entity. High AR expression and high rates of dysregulation along the PIK3CA/AKT/mTOR pathway are consistent with recent reports in the literature.
Citation Format: Raquel A. Nunes, David Arguello, Zoran Gatalica, Sandeep Reddy, Sandra M. Swain. Multiplatform molecular profiling of invasive lobular breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 123.
Abstract 1236: ONC201 sensitivity profiling indicates pronounced sensitivity in lymphoid, prostate, colon and brain tumors
Authors: Tarapore Rohinton , Garnett Mathew , McDermott Ultan , Benes Cyril , Allen Joshua 
Published: July 2016

Abstract
ONC201 is a first-in-class small molecule inducer of the integrated stress response that is currently in phase II clinical trials in select advanced cancers and exhibits a benign safety profile and promising early clinical results. The efficacy of this novel agent has been demonstrated in a variety of preclinical advanced cancer models in multiple indications with an exceptional safety profile that has translated well to the clinic. To better characterize the differential sensitivity of tumor cells to ONC201 we performed in vitro efficacy assays in the Genomic of Drug Sensitivity in Cancer collection of cell lines (&gt;1,000 cell lines), in addition to profiling in NCI60 panel. Sensitivity profiling was assessed by cell viability assays using dose responses curves at concentrations up to 20uM and at 72 hours post-treatment. Ranking the sensitivity dataset by tumor type revealed that lymphoma, colon, prostate and brain cancers were highly responsive to ONC201. The strongest predictor of sensitivity to ONC201 was tumor type, with lymphoma being the strong predictor. Within lymphomas, diffuse histiocytic lymphoma was the most sensitive subtype. Mutations that are frequent in lymphoma were not associated with ONC201 sensitivity.
Recent mechanistic studies have implicated the ER stress response in the early stage mechanism of ONC201 that triggers its downstream antitumor effects. The mutation-agnostic efficacy that is pronounced in lymphomas, prostate, colon, and brain cancers is in accordance with the recent findings that ONC201 induces the integrated stress response through a novel target to trigger is downstream late apoptotic effects. Cancers of the prostate and brain (glioblastoma multiforme) are among some of the solid tumors that are susceptible to induction of apoptosis via the integrated stress response, as they have relatively high basal activation of this pathway due to ER stress. Confirmatory studies revealed that brain cancer cell lines and ex vivo samples indeed possess pronounced sensitivity with nanomolar GI50s, unlike most other tumor types, which is particularly encouraging given the systemic concentrations observed in the first-in-man study. Together, these studies suggest specific advanced cancer indications, such as non-Hodgkin's lymphoma, multiple myeloma, and glioblastoma as promising lead indications for this novel agent that are being evaluated in phase II clinical trials.
Citation Format: Rohinton Tarapore, Mathew Garnett, Ultan McDermott, Cyril Benes, Joshua Allen. ONC201 sensitivity profiling indicates pronounced sensitivity in lymphoid, prostate, colon and brain tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1236.
Abstract 1241: Podophyllotoxin acetate (PA) as an anti-cancer drug candidate regulates various malignancy traits of non-small cell lung cancer
Authors: Cho Jeong Hyun , Hong Wan Gi , Hwang Sang-Gu , Um Hong-Duck , Park Jong Kuk 
Published: July 2016

Abstract
Here, we reported that podophyllotoxin acetate (PA) showed various aniti-cancer effects: induction of several cell death pathways, inhibition of γ-ionizing radiation (IR)-induced cancer invasion, chemo-sensitizer effect with topoisomerase (TOP) inhibitors against non-small cell lung cancer (NSCLC) cell lines as follows. (1) Stimulation of cell death via various mechanisms. First, PA dose-dependently induced cell cycle arrest at G2/M phase, as shown by accumulation of the mitosis-related proteins, p21, survivin and aurora B. This arrest was due to the PA-induced inhibition of microtubule polymerization that related to DNA damage (reflected by accumulation of γ-H2AX) resulting induction of intrinsic/extrinsic damage apoptotic pathways. PA also activated the pro-apoptotic ER stress pathway, as evidenced by increased expression levels of BiP, CHOP, IRE1-a, phospho-PERK, and phospho-JNK. Next, PA induced autophagy that reflected the expression of beclin-1, Atg3, Atg5 and Atg7, and the cleavage of LC3. (2) Inhibition of IR-induced cancer invasion. IR increased the invasion/migration of A549 cells, and this effect was decreased by PA treatment that the expressions/activities of matrix metalloprotase (MMP) -2, MMP-9, and vimentin, suggesting that PA could block the IR-induced epithelial-mesenchymal transition (EMT). In this study, we also identified IR-induced new signaling pathway, EGFR - p38/ERK - CREB-1/STAT3 - EMT pathway, that was inhibited by PA. (3) Chemo-sensitizer effect conjugated with TOP inhibitors - etoposide (Eto) and camptothecin (Cpt). Combination Index (CI) values of the combinations showed synergistic effects between PA and topoisomerase inhibitors. Combination with PA and Eto/Cpt promotes disruption of dynamics of actin filaments, which subsequently enhanced apoptotic cell death that accompanied to increased phosphorylation of p38. We also observed these combinations also inhibited activation of CREB-1, synergistically. Therefore, this study indicated that PA functions as a chemosensitizer by enhancing apoptosis through activation of p38/caspases apoptotic axis and suppression of CREB-1.Taken together; these results suggest PA is a new anti-cancer drug candidate that could control several malignancy traits of cancer including uncontrolled cell cycle and IR-induced invasion.
Citation Format: Jeong Hyun Cho, Wan Gi Hong, Sang-Gu Hwang, Hong-Duck Um, Jong Kuk Park. Podophyllotoxin acetate (PA) as an anti-cancer drug candidate regulates various malignancy traits of non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1241.
Abstract 1245: RRx-001 is effective in temozolomide-sensitive and resistant GBM
Authors: Steri Veronica , Oronsky Bryan , Scicinski Jan , Bergers Gabriele 
Published: July 2016

Abstract
Glioblastoma Multiforme (GBM) is one of the most aggressive malignancies in humans, being highly invasive and drug-resistant, limiting the effectiveness of surgery, chemotherapy and radiotherapy. Concurrent Temozolomide (TMZ) and radiation is the standard of care for newly diagnosed GBM patients, however, patients respond poorly and prognosis remains dismal. TMZ response is limited to patients with hypermethylation of the methylguanine methyltransferase (MGMT) promoter. Despite recent advances in therapeutic strategies, treating GBM is still an unsolved clinical challenge requiring the investigation of novel approaches with better responses over approved therapies. RRx-001 is a novel ROS-mediated systemically non-toxic chemo-sensitizing epigenetic agent with vascular normalizing properties under investigation in Phase II clinical trials in brain metastases and GBM.
We assessed whether RRx-001 is an effective approach for treating GBM by testing its effects alone and in combination with TMZ both in vitro as well as in GBM mouse models. RRx-001 induced cytotoxicity in human TMZ-sensitive as well as resistant patient-derived GBM cell lines. In addition, its effect in TMZ-sensitive GBM cells was greater than the one induced by TMZ alone.
We then asked whether the in vitro effects of RRx-001 translated to therapeutic efficacy in vivo. To this end, we injected mice intracranially with a TMZ-resistant murine mesenchymal GBM cells, and treated tumor-bearing mice with RRx-001 alone and in combination with TMZ. RRx-001 treatment alone modestly prolonged survival compared to control cohorts, whereas the combination of RRx-001 and TMZ substantially prolonged survival compared to controls and either treatment alone. Moreover, histological evaluation of GBM tumors revealed that combination of RRx-001 and TMZ induced vessel hyperdilation and apoptosis compared to RRx-001 alone. Thus, in vivo RRx-001 combined to TMZ may also indirectly regulate tumor growth by modifying the tumor stroma.
These data suggest that TMZ may still affect the microenvironment in TMZ-resistant tumors and that RRx-001 enhances these effects by both directly and indirectly restricting GBM growth, making it a promising therapeutic agent alone and in combination with TMZ.
Citation Format: Veronica Steri, Bryan Oronsky, Jan Scicinski, Gabriele Bergers. RRx-001 is effective in temozolomide-sensitive and resistant GBM. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1245.
Abstract 1250: Antitumor activities of CD161, a structurally novel and orally bioavailable BET inhibitor, in leukemia and triple negative breast cancer cells in vitro and in vivo
Authors: Bai Longchuan , Zhao Yujun , Liu Liu , Yang Chao-Yie , McEachern Donna , Stuckey Jeanne , Meagher Jennifer , Wen Bo , Sun Duxin , Wang Shaomeng 
Published: July 2016

Abstract
Bromodomain and extraterminal (BET) proteins, such as bromodomain-containing protein 2 (BRD2), BRD3 and BRD4, bind lysine acetylated proteins and regulate gene transcription. Several BET inhibitors are currently under clinical development for hematological malignancies and solid tumors. We have recently developed a novel class of BET inhibitor, CD161, which binds the bromodomain 1 (BD1) and BD2 domains of BRD2, BRD3, BRD4 and BRDT with Ki less than 10 nM. Co-crystal structure of CD161 and BRD4 BD2 at 2.5 Å resolution confirmed that the docked CD161 occupies the acetyl-lysine binding pocket of BD2. CD161 has &gt;1000-fold selectivity over other bromodomain containing proteins including CREBBP, ATAD2B, TRIM24 and ASH1L. In human leukemia cell lines MV4-11 and MOLM-13, CD161 strongly inhibits cell growth and induces apoptosis, with IC50s &lt;100 nM. Furthermore, CD161 exerts potent growth-inhibitory activities in a panel of breast cancer cell lines representative of triple-negative breast cancer (TNBC), with IC50s in the sub micromolar range. At 20-50 mg/kg daily oral dosing for 2 weeks, CD161 significantly inhibited the growth of MV4-11 and MDA-MB-231 tumors (TGI: 55-80%) in mouse xenograft models and had no significant effect on body weights. Pharmacokinetics studies show that CD161 has a T1/2 of 2-3 hours and oral bioavailability (F%) of 93% in male Sprague−Dawley rats. Transcriptional profiling revealed that CD161 causes broad transcriptional changes in TNBC cell lines. Our preliminary results suggest the therapeutic potential of CD161 in human leukemia and TNBC.
Citation Format: Longchuan Bai, Yujun Zhao, Liu Liu, Chao-Yie Yang, Donna McEachern, Jeanne Stuckey, Jennifer Meagher, Bo Wen, Duxin Sun, Shaomeng Wang. Antitumor activities of CD161, a structurally novel and orally bioavailable BET inhibitor, in leukemia and triple negative breast cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1250.
Abstract 1251: Significant growth suppressive effects of TOPK and MELK inhibitors in kidney cancer
Authors: Kato Taigo , Inoue Hiroyuki , Imoto Seiya , Tamada Yoshinori , Miyamoto Takashi , Matsuo Yo , Nakamura Yusuke , Park Jae-Hyun 
Published: July 2016

Abstract
Kidney cancer is the seventh most common cancer and the tenth most common cause of cancer death for men, and it is the tenth most common cause of cancer for women. The 5-year disease-specific survival has improved from about 50% in 1975-1977 to 65% in 2000-2005, although that of patients at an advanced stage still remains poor with less than 10%; 30% of patients who underwent surgery of localized kidney cancer develop distant metastasis and have limited therapeutic options such as tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors. In addition, the clinical effects of these drugs are limited and patients often discontinue these drugs due to severe side effects including hand-foot syndrome, liver dysfunction and interstitial pneumonia. Therefore, development of more effective therapy for kidney cancer is eagerly expected. T-lymphokine-activated killer cell-originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) are promising molecular targets that play critical roles in cancer cell proliferation and maintenance of their stemness. In this study, we investigated growth promotive effect of TOPK and MELK in kidney cancer and found a complex feedback mechanism of these two molecules. Blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cell. On the other hand, knockdown and overexpression of FOXM1 caused downregulation and upregulation of both TOPK and MELK mRNA levels, respectively, suggesting that FOXM1 is a critical transcriptional factor for these two molecular targets. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth and the combination of these two compounds additively induced the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 should produce synergistic anti-tumor effects with low risk of side effects.
Citation Format: Taigo Kato, Hiroyuki Inoue, Seiya Imoto, Yoshinori Tamada, Takashi Miyamoto, Yo Matsuo, Yusuke Nakamura, Jae-Hyun Park. Significant growth suppressive effects of TOPK and MELK inhibitors in kidney cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1251.
Abstract 1253: Inhibition of FN14 to suppress KRAS-driven lung cancer migration and survival
Authors: Carson Vashti M. , Kim Seungchan , Inge Landon J. , Whitsett Timothy G. 
Published: July 2016

Abstract
Lung cancer remains the leading cause of cancer related mortality throughout the world, and is estimated to kill more than one million people this year. Mutations in KRAS occur in about 1/3 of all lung adenocarcinomas, the most common histologic subtype of lung cancer. Mutations in KRAS are correlated with poor patient prognosis, advanced disease, therapeutic resistance and metastatic outcomes. There is an unmet clinical need to target KRAS-driven NSCLC towards abating the high mortality rate of this disease. We hypothesize that the tumor necrosis factor receptor, FN14 is induced and sustained by mutant KRAS signaling, and represents a therapeutic target in KRAS-driven NSCLC. Employing The Cancer Genome Atlas (TCGA) data, we showed that within a subgroup of adenocarcinoma patients harboring mutant KRAS, elevated FN14 expression conferred significantly worse survival outcomes compared to those with lower FN14 expression. Alone, elevated expression of FN14 conferred a poor prognosis in adenocarcinoma patients compared to lower expression of FN14. In lung cancer cell lines driven by mutant KRAS, elevated FN14 protein expression was observed. The ectopic induction of mutant KRAS in normal rat lung epithelial cells was sufficient to induce FN14 protein expression, an induction dependent on ERK signaling. In an animal model of mutant KRAS-driven NSCLC, FN14 protein was highly expressed and correlated with metastasis in vivo. TWEAK, the only known ligand for FN14, induced migration in NSCLC cell lines harboring mutant KRAS. Conversely, depletion of FN14 expression through siRNA suppressed KRAS-driven cell migration in vitro. We further demonstrated using a clonogenic assay that depletion of FN14 by siRNA was sufficient to reduce KRAS-driven NSCLC cell survival and significantly enhanced the cell killing effects of standard-of-care treatments such as radiation or cisplatin. These data suggest that NSCLC tumors harboring mutant KRAS may be vulnerable to inhibition of FN14 signaling. The recent development of FN14-targeted therapeutics provides an avenue towards clinical utility. As no therapeutics exist to target KRAS directly, a therapeutic strategy targeting FN14 might impact survival in KRAS-driven tumors and reduce the high mortality rate in this subgroup.
Citation Format: Vashti M. Carson, Seungchan Kim, Landon J. Inge, Timothy G. Whitsett. Inhibition of FN14 to suppress KRAS-driven lung cancer migration and survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1253.