bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL03-04: Protein methyltransferase inhibitors as personalized cancer therapeutics.
Authors: Copeland Robert A. 
Published: August 2014

Abstract
The protein methyltransferases (PMTs) constitute a class of enzymes that catalyze the methylation of lysine or arginine residues on histones and other proteins. A number of PMTs have been shown to be genetically altered in cancers through, for example, gene amplification, chromosomal translocations, point mutations and synthetic lethal relationships. The enzymes DOT1L and EZH2 provide two representative examples of altered PMTs that act as genetic drivers of specific human cancers. The enzymatic activity of DOT1L is associated with a chromosomal translocation that is universally found in patients with MLL-rearranged leukemia. Point mutations at Y641 of EZH2 are found in a subset of non-Hodgkins lymphoma patients; the enzymatic activity of both wild type and mutant EZH2 are required for pathogenesis in these patients. Also, deletion of the INI1 (SMARCB1 or hSNF5) subunit of the SWI/SNF chromatin-remodeling complex occurs in nearly all malignant rhabdoid tumors (MRTs), a childhood cancer with a particularly poor prognosis. An antagonistic relationship has been demonstrated between the biochemical action on chromatin of the SWI/SNF complex and EZH2 (in the context of the polycomb repressive complex 2), that is relieved in MRTs due to the INI1 deletion. MRTs therefore demonstrate increased reliance on the enzymatic activity of EZH2 for proliferation and we have shown that MRT cells deficient in INI1 are selectively killed by inhibition of EZH2 in cell culture and in mouse xenograft models. Drug discovery efforts have yielded potent, selective inhibitors of each of these targets that have now transitioned into Phase I clinical trials. These inhibitors affect the appropriate histone methyl marks in cells, lead to selective cell killing that is dependent on genetic alteration of the target enzyme and effect tumor growth inhibition in xenograft models. These data portend the effective use of selective PMT inhibitors as a novel modality for future personalized cancer therapeutics.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL03-04.
Citation Format: Robert A. Copeland. Protein methyltransferase inhibitors as personalized cancer therapeutics. [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 PL03-04.
Abstract PL04-02: Targeting MEK in KRAS mutant lung cancer.
Authors: Jänne Pasi A. 
Published: August 2014

Abstract
Despite all of the success in targeted therapies for NSCLC, treatment of KRAS mutant NSCLC has been much more challenging. In Caucasian patients, KRAS mutant NSCLC is the most common subset of NSCLC. Therapeutic development of agents specifically targeting KRAS have been unsuccessful. However, recent preclinical and clinical studies suggest that targeting MEK may have some efficacy in KRAS mutant NSCLC.
MEK inhibitors selumetinib (AZD6244) and trametinib (GSK1120212) are undergoing clinical development in previously treated KRAS mutant NSCLC patients. A randomized phase II clinical trial of selumetinib/docetaxel vs. docetaxel demonstrated a significant improvement in radiographic response (RR) rate (37% vs. 0%) and progression free survival (PFS) (5.3 vs. 2.1 months) and a numerical increase in overall survival (OS) (9.4 vs. 5.2 months) all in favor of the selumetinib combination. A phase III trial comparing selumetinib/docetaxel to docetaxel alone is currently underway. The trametinib study compared single agent trametinib to docetaxel in a similar patient population. In this study, the PFS was similar for both trametinib and docetaxel (11.7 and 11.4 weeks, respectively) as was the RR (12% in each arm). Additional studies are underway.
Recent preclinical studies also suggest that the presence or absence of the tumor suppressor gene, LKB1, may impact the efficacy of selumetinib/docetaxel in a murine model of KRAS mutant NSCLC. LKB1 loss is detected in ∼ 30% of KRAS mutant cancers. In addition, there may be differences in patient outcomes based on the subtype of KRAS mutations. The impact and strategies to evaluate LKB1 loss and the subtypes of KRAS mutations in ongoing clinical trials of MEK inhibitors will be discussed.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL04-02.
Citation Format: Pasi A. Jänne. Targeting MEK in KRAS mutant lung cancer. [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 PL04-02.
Abstract PL04-04: Synthetic lethal approaches to targeting Ras mutant cancers.
Authors: Downward Julian 
Published: August 2014

Abstract
The RAS oncogenes are very frequently activated by mutation in human tumors, which very often show continued dependency on the signaling functions of RAS. In addition to controlling the RAF/MEK/ERK pathway, RAS proteins are established to be important direct regulators of type I phosphoinositide 3-kinases (PI3Ks), interacting via an amino terminal RAS binding domain (RBD). Disruption of PI3K p110alpha activation by oncogenic KRAS has been shown to prevent tumor development in a mouse model of lung cancer. Disruption of RAS-PI3K p110alpha interaction in established lung tumors prevents tumor progression and results in long-term stabilization of lung tumors. Coordinate inhibition of the MAPK pathway at the same time promotes tumor regression and dramatically reduces tumor burden. However, as yet it is unclear whether the combined targeting of pathways that RAS controls, such as RAF/ERK and PI 3-kinase/AKT, will prove effective in the treatment of RAS mutant cancers in the clinic, or whether this approach will prove unacceptably toxic. It is therefore important that other means of targeting this critical oncogene are considered. One such approach is the development of agents that directly inhibit the function of RAS proteins, for example by blocking interaction with effectors. Another approach, which will be explored here, is the identification of unique dependencies of RAS mutant tumor cells through the use of functional genomic screens. We have used RNA interference libraries on a panel of lung cancer cell lines to determine genes that are required for the survival of cells with oncogenic KRAS mutations, but not wild type KRAS. This has led to the identification of signaling networks that are essential for RAS mutant cells, including a transcriptional programme controlled by the GATA2 transcription factor. In mouse models of lung cancer, deletion of GATA2 leads to dramatic regression of RAS induced tumors. Although GATA2 itself is likely to be undruggable, investigation of the transcriptional targets of GATA2 has revealed three key pathways that are much more tractable: the proteasome, NF-kB and Rho signaling. Combined suppression of GATA2 regulated pathways with clinically approved inhibitors of the proteasome and Rho kinase causes marked tumor clearance. Discovery of the non-oncogene addiction of KRAS mutant lung cancers to GATA2 function presents a network of druggable pathways for therapeutic exploitation. We are currently testing combinations of GATA2 functional targeting with other approaches that show potential, such as MEK plus PI 3-kinase inhibition, and immune checkpoint modulators.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL04-04.
Citation Format: Julian Downward. Synthetic lethal approaches to targeting Ras mutant cancers. [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 PL04-04.
Abstract PL05-01: Heterogeneity in DCIS and invasive breast cancers.
Authors: Polyak Kornelia 
Published: August 2014

Abstract
Intratumor genetic and phenotypic heterogeneity of cancer cells underlies tumor progression and therapeutic resistance; thus, it is a major clinical problem. We have characterized intratumor genetic and phenotypic heterogeneity by immunoFISH (iFISH) in DCIS (ductal carcinoma in situ), primary invasive tumors, lymph node and distant metastases, as well as breast tumor biopsies before and after treatment. We found the highest genetic diversity in distant metastases but surprisingly these lesions were less divergent than primary-lymph node pairs. Intratumor diversity was also associated with tumor subtype and response to treatment. We also developed preclinical models to address the functional relevance of intratumor clonal heterogeneity in breast cancer and found cooperative interactions that promote tumor growth and metastatic progression. Our analyses of clonal frequency and drivers of tumor growth have revealed some unexpected findings. Our results emphasize the need to understand the cancer cell populations that compose tumors to be able to predict tumor evolution.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL05-01.
Citation Format: Kornelia Polyak. Heterogeneity in DCIS and invasive breast cancers. [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 PL05-01.
Abstract PL06-03: Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing.
Authors: Sausen Mark 
Published: August 2014

Abstract
Clinical management of cancer patients could be improved through the development of noninvasive approaches for the detection of incipient, residual, and recurrent tumors. We describe an approach to directly identify tumor-derived chromosomal alterations through analysis of circulating cell-free DNA from cancer patients. Whole-genome analyses of DNA from the plasma of colorectal and breast cancer patients and healthy individuals with massively parallel sequencing identified, in all patients, structural alterations that were not present in plasma DNA from healthy subjects. Detected alterations comprised chromosomal copy number changes and rearrangements, including amplification of cancer driver genes such as ERBB2, MET, and CDK6. The level of circulating tumor DNA in the cancer patients ranged from 1.4 to 47.9%. The sensitivity and specificity of this approach are dependent on the amount of sequence data obtained and are derived from the fact that most cancers harbor multiple chromosomal alterations, each of which is unlikely to be present in normal cells. Given that chromosomal abnormalities are present in nearly all human cancers, this approach represents a useful method for the noninvasive detection of human tumors that is not dependent on the availability of tumor biopsies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL06-03.
Citation Format: Mark Sausen. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. [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 PL06-03.
Abstract PL08-03: Melanoma Research Alliance: Investing in innovation.
Authors: Perkins Louise M. 
Published: August 2014

Abstract
Melanoma is the deadliest of all skin cancers with more than 132,000 new cases each year worldwide and rising incidence. In the United States alone, melanoma incidence has tripled over the past three decades and it now represents the fifth most common cancer in men and the seventh most common in women. More than 76,690 new cases and more than 9,480 deaths are expected in the United States in 2013. Alarmingly, melanoma is the second most frequently diagnosed cancer among young adults in the U.S.
Historically, treatment options for patients with metastatic melanoma have been severely limited, but recent advances have considerably changed the landscape. In 2011, two new drugs were approved by the FDA for metastatic melanoma, ipilimumab and vemurafenib, providing the proof-of-concept for use of immunotherapy as well as targeted therapy in metastatic melanoma. Progress in treatment has continued with the 2013 approval of two additional drugs for patients with BRAF mutations, trametinib and dabrafenib. While these newly approved drugs alone will not cure most patients (although a small subset of patients have experienced longer term durable benefit from them), they establish the foundation for new, more successful approaches. Moreover, genomics studies have revealed a large number of drug targets for melanoma that offer significant opportunity to avert or treat drug resistant disease as well as for personalized medical approaches. As a result, there is unprecedented transformational progress on behalf of patients highlighted by the more than 100 new melanoma drugs in the pipeline, with nearly 300 clinical trials underway.
MRA-funded researchers are working to improve the success of the current therapies by identifying new biomarkers, combining treatments aimed at countering drug resistance, as well as discovering new and more effective drug targets for melanoma. By promoting collaboration in the field and providing critical investments in innovative translational research, MRA is at the forefront of these advances.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL08-03.
Citation Format: Louise M. Perkins. Melanoma Research Alliance: Investing in innovation. [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 PL08-03.
Abstract PR04: BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition.
Authors: Hutchinson Katherine , Lipson Doron , Stephens Philip J. , Otto Geoff , Lyle Pamela L. , Vnencak-Jones Cindy L. , Ross Jeffrey S. , Sosman Jeffrey A. , Puzanov Igor , Miller Vincent A. , Pao William 
Published: August 2014

Abstract
Recurrent “driver” mutations at specific loci in BRAF, NRAS, KIT, GNAQ, and GNA11 define clinically-relevant molecular subsets of melanomas, but &gt;30% are “pan-negative” for these recurrent mutations. Through next-generation sequencing (NGS), we identified a novel PAPSS1-BRAF fusion in a “pan-negative” melanoma. Characterization of oncogenic, transforming BRAF fusions have been described previously in cancer, but not yet in melanoma. Activation of the mitogen-activated protein kinase (MAPK) pathway in cells by ectopic expression of PAPSS1-BRAF can be abrogated by MEK inhibition but not by BRAF inhibition. Analysis of 51 additional melanomas revealed a second MEK inhibitor-sensitive BRAF fusion (TRIM24-BRAF), also in a “pan-negative” sample. Collectively, our data suggest that BRAF fusions define a new molecular subset of melanoma, comprising 8% of “pan-negative” cases, which may benefit from treatment with kinase inhibitors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR04.
Citation Format: Katherine Hutchinson, Doron Lipson, Philip J. Stephens, Geoff Otto, Pamela L. Lyle, Cindy L. Vnencak-Jones, Jeffrey S. Ross, Jeffrey A. Sosman, Igor Puzanov, Vincent A. Miller, William Pao. BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. [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 PR04.
Abstract PR06: A functional screen of the epigenome identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers.
Authors: Jagani Zainab , Hoffman Gregory , Rahal Rami , Buxton Frank , McAllister Gregory , Xiang Kay , Frias Elizabeth , Huber Janina , Lindeman Alicia , Chen Dongshu , Bagdasarian Linda , Romero Rodrigo , Ramadan Nadire , Phadke Tanushree , Haas Kristy , Jaskelioff Mariela , Wilson Boris , Meyer Matthew , McLaughlin Margaret E. , Roberts Charles WM , Myer Vic , Porter Jeff , Keen Nicholas , Mickanin Craig , Stegmeier Frank 
Published: August 2014

Abstract
Epigenetic dysregulation is an emerging hallmark of cancers, and the identification of recurrent somatic mutations in chromatin regulators implies a causal role for altered chromatin states in tumorigenesis. As the majority of epigenetic mutations are inactivating and thus do not present directly druggable targets, we reasoned that these mutations may alter the epigenomic state of cancer cells and thereby expose novel epigenetic vulnerabilities. To systematically search for epigenetic synthetic lethal interactions, we performed a deep coverage pooled shRNA screen across a large collection of cancer cell lines using a library targeting a diverse set of epigenetic regulators. Strikingly, this unbiased screen revealed that silencing of the SWI/SNF ATPase subunit BRM/SMARCA2, selectively inhibits the proliferation of BRG1-deficient cancer cells. The mammalian SWI/SNF complexes (mSWI/SNF) regulate chromatin structure through ATP-dependent nucleosome remodeling. Recent cancer genome studies have revealed a significant frequency of mutations in several components of the mSWI/SNF complexes including loss of the catalytic subunit BRG1 in non-small cell lung cancers. Our studies reveal that BRM knockdown selectively induced cell cycle arrest in BRG1-mutant cancer cells and significantly impaired the growth of BRG1-mutant lung tumor xenografts. BRM is the paralog of BRG1, suggesting a model in which mSWI/SNF mutations lead to a hypomorphic complex that promotes tumorigenesis but cannot tolerate complete inactivation. Therefore, our studies present BRM as an attractive therapeutic target in BRG1-mutant cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR06.
Citation Format: Zainab Jagani, Gregory Hoffman, Rami Rahal, Frank Buxton, Gregory McAllister, Kay Xiang, Elizabeth Frias, Janina Huber, Alicia Lindeman, Dongshu Chen, Linda Bagdasarian, Rodrigo Romero, Nadire Ramadan, Tanushree Phadke, Kristy Haas, Mariela Jaskelioff, Boris Wilson, Matthew Meyer, Margaret E. McLaughlin, Charles WM Roberts, Vic Myer, Jeff Porter, Nicholas Keen, Craig Mickanin, Frank Stegmeier. A functional screen of the epigenome identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. [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 PR06.
Abstract 1760: Preclinical evaluation of IMGN853, an anti-FOLR1 antibody-maytansinoid conjugate, as a potential therapeutic for ovarian cancer
Authors: Whiteman Kathleen R. , Johnson Holly A. , Xu Shanqin , Carrigan Christina N. , Ab Olga , Pinkas Jan 
Published: August 2014

Abstract
IMGN853 (M9346A-sulfo-SPDB-DM4) is an antibody drug-conjugate consisting of the cytotoxic maytansinoid, DM4, covalently linked to the humanized monoclonal antibody M9346A, which selectively binds to folate receptor 1 (FOLR1). FOLR1 is over-expressed on ovarian cancers (38 of 67 tumor samples positive for FOLR1 ∼ 57%) suggesting that ovarian cancer may be a primary indication for clinical development of IMGN853.
FOLR1 expression was evaluated on a panel of ovarian cancer xenografts and human ovarian tumors using a calibrated immunohistochemical (IHC) staining method on formalin-fixed paraffin-embedded sections. The FOLR1 expression levels and patterns in three ovarian adenocarcinoma xenografts, OVCAR-3, IGROV-1 and OV-90, were consistent with those observed in FOLR1-positive patient ovarian tumor samples.
The anti-tumor activity of IMGN853 was evaluated in the three FOLR1-positive ovarian xenograft models identified. CB.17 SCID mice bearing established subcutaneous xenograft tumors (approximately 100 mm3) were treated with a single intravenous injection of IMGN853 at 1.2, 2.5 and 5.0 mg/kg (based on antibody concentration). IMGN853 was active in all three models evaluated. In OVCAR-3 xenografts, the minimally efficacious dose (MED) of IMGN853 was 1.2 mg/kg. The higher dose levels were highly active, resulting in complete regressions (CR) in 4/6 and 6/6 mice in the 2.5 and 5.0 mg/kg treatment groups, respectively. Treatment with IMGN853 resulted in strong anti-tumor activity in both IGROV-1 and OV-90 xenograft models, with a MED of 2.5 mg/kg, single injection.
The strong anti-tumor activity of IMGN853 against ovarian xenograft tumors with FOLR1 expression levels comparable to patient tumors suggests that IMGN853 may be a promising candidate for clinical development in ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1760. doi:10.1158/1538-7445.AM2011-1760
Abstract 2: IGF-1 attenuates antiestrogen- and antiprogestin-induced apoptosis in ER + breast cancer cells by MEK1 regulation of the BH3-only pro-apoptotic protein Bim
Authors: Takhar Suchreet , Periyasamy-Thandavan Sudharsan , Jackson William Hutch , Huang Shuang , Schoenlein Patricia 
Published: August 2014

Abstract
In an effort to understand the underlying mechanisms of inherent antiestrogen resistance in estrogen receptor positive (ER+) breast cancer cells, we have been studying the pro-survival role of insulin-like growth factor 1 (IGF-1) in protecting breast cancer cells from death induced by hormonal therapy. In past studies, we demonstrated that IGF-1, at physiologically relevant doses binds the insulin like growth factor receptor (IGF-IR), blocks antiestrogen- and antiprogestin- induced apoptosis in ER+ MCF-7 breast cancer cells. We further showed that the mechanism of protection was dependent on the action of the dual specificity protein kinase MEK1 (Abstract #4846, Proc Am Assoc Cancer Res, 51, 2010, p1178-79); however we did not elucidate the specific death effector pathway being blocked by MEK1/MAPK signaling. For this study, we sought to identify the specific death pathway blocked by the IGF-IR/MEK1/MAPK prosurvival signaling. We now present strong data identifying the pro-apoptotic BH3 family member Bim as a critical death effector activated by MEK1 blockade in ER+ breast cancer cells. We utilized Bim siRNA, which effectively down-regulated Bim intracellular protein expression by five-to ten-fold. Bim downregulation significantly attenuated the pro-apoptotic action(s) of U0126, as well as that of the antiestrogen 4-hydroxytamoxifen (4-OHT) and/or the antiprogestin mifepristone (MIF). Bim knockdown reduced the generation of ROS that results from treatment with 4-OHT, MIF, and U0126 (whether used as monotherapies or in combination) and is required for MCF-7 apoptotic cell death under these treatment conditions. We are currently elucidating how Bim action induces cell death in breast cancer cells with compromised MEK1 action. These studies support the targeting of MEK1 to activate a Bim-dependent apoptotic pathway during hormonal therapy of early-stage breast cancer, particularly in patients with high circulating levels of IGF-1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2. doi:10.1158/1538-7445.AM2011-2