Search

In men with advanced penile squamous cell carcinoma receiving first-line chemotherapy, visceral metastases (VM) and Eastern Cooperative Oncology Group performance status ≥1 are poor prognostic factors for overall survival (OS). We hypothesized that tumor gene expression profiling may enhance prognostic stratification and identify potential therapeutic targets. In this retrospective study, RNA extracted from macrodissected tumors underwent profiling for the expression of 738 genes using NanoString. Univariate and multivariate analyses assessed the association of genes, VM, and performance status with OS. Tumors were available from 25 men who received first-line cisplatin-based chemotherapy. In univariate analysis, upregulated MAML2 ( p =0.004), KITLG ( p ≤0.0001), and JAK1 ( p =0.029) genes were associated with poor OS, and upregulated FANCA was associated with better OS ( p =0.024). In stepwise multivariate analyses, VM (hazard ratio=12.75, p =0.0001) and MAML2 (hazard ratio=10.411, p =0.003) were associated with poor OS. The presence of none, one, and both of these poor risk factors was associated with significantly different median OS of 18.4 mo, 7.2 mo, and 2.1 mo, respectively. Unsupervised clustering demonstrated two major molecular subtypes with trend for different survivals ( p =0.052). Validation of results is necessary. Patient summary The expression of the MAML2 gene in penile cancers from men receiving first-line cisplatin-based chemotherapy predicted overall survival independent of clinical factors.

Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p

Background: Epidermal growth factor receptor (EGFR) overexpression is present in 80-100% of head and neck cancers, and targeting EGFR with cetuximab has improved outcomes when combined with radiotherapy (XRT). However, over half of these patients still succumb to this disease, necessitating novel therapies. Checkpoint kinase 1 and 2 (Chk1/2) are serine/threonine kinases that prevent cell cycle progression and serve as critical regulators of the DNA-damage response. LY2606368 monomesylate monohydrate (CHKi), a potent inhibitor of Chk1/2, exhibits single agent activity in tumors of squamous cell histology, including head and neck. Because of the role of Chk1/2 in DNA damage response, we hypothesized that CHKi may enhance the cytotoxicity induced by cetuximab and XRT in head and neck cancer. Methods: The HPV-negative UM-SCC1 and HPV-positive UM-SCC47 head and neck cancer cells were used. Doses of drug compounds are as follows: CHKi (LY2606368, Eli Lilly) 1nM; Cetuximab 0.25μg/mL. Cell proliferation was assessed using a Beckman Coulter Counter. Clonogenic survival was measured with colony formation assays. Apoptosis was analyzed using Annexin V-FITC staining and western blot analysis for cleaved and full length caspase-3 and 9. DNA damage and checkpoint signaling was investigated via western blot analysis for phospho- and total Chk1, Chk2, ATM, ATR, and γ-H2AX. Animal studies were performed using orthotopic tongue injection of UM-SCC1-Luc or heterotopic flank injection of UM-SCC47 cells in athymic nude mice, which were then subjected to 3 cycles of once-weekly CHKi (4mg/kg), cetuximab (0.1mg), and 2Gy XRT. Results: The addition of CHKi to cetuximab and XRT resulted in the greatest reduction of cell proliferation and increased cytotoxicity in both HPV positive (HPV+) UM-SCC47 and HPV negative (HPV-) UM-SCC1 cancer cells in vitro. Triple combination treatment effectively reduced cell growth by ∼89% in UM-SCC1 and ∼63% in UM-SCC47 at 96hrs compared to untreated cells. A robust decrease in clonogenic survival in both cell lines was also observed (approximately 90% at 2Gy). Furthermore, this combination abrogated the DNA damage checkpoints induced by cetuximab and XRT, resulting in persistent DNA damage and activation of apoptosis. Specifically, we observed CHKi-mediated downregulation of total and phospho- Chk1, Chk2, ATR, and ATM, with concomitant increases in cleaved caspase-3 and caspase-9. Importantly, combining CHKi, cetuximab, and XRT led to a significant tumor growth delay in mice bearing orthotopic or heterotopic head and neck tumor xenografts compared to control mice. Additionally, no significant weight loss or toxicity was observed in the treatment. Conclusions: CHKi enhanced the in vitro and in vivo cytotoxicity of cetuximab and XRT against human head and neck tumor models. A clinical trial to test this treatment for head and neck cancer patients is underway (NCT02555644). Citation Format: Ling Zeng, Reena Beggs, Tiffiny Cooper, Eddy Shih-Hsin Yang. Combining Chk1/2 inhibition with cetuximab and irradiation enhances in vitro and in vivo cytotoxicity of head and neck cancer models. [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 3046.

Few therapeutic options exist for the highly aggressive triple negative breast cancers (TNBCs). In this study, we report that a contextual synthetic lethality can be achieved both in vitro and in vivo with combined EGFR and PARP inhibition with lapatinib and ABT-888, respectively. The mechanism involves a transient DNA double strand break repair deficit induced by lapatinib and subsequent activation of the intrinsic pathway of apoptosis. Further dissection of the mechanism reveals that EGFR and BRCA1 can be found in the same protein complex, which is reduced by lapatinib. Interestingly, lapatinib also increases cytosolic BRCA1 and EGFR, away from their nuclear DNA repair substrates. Taken together, these results reveal a novel regulation of homologous recombination repair involving EGFR and BRCA1 interaction and alteration of subcellular localization. Additionally, a contextual synthetic lethality may exist between combined EGFR and PARP inhibitors.

HER2 overexpression in breast cancer confers increased tumor aggressiveness. Although anti-HER2 therapies have improved patient outcome, resistance ultimately occurs. PARP inhibitors target homologous recombination (HR)-deficient tumors, such as the BRCA-associated breast and ovarian cancers. In this study, we show that HER2+ breast cancers are susceptible to PARP inhibition independent of an HR deficiency. HER2 overexpression in HER2 negative breast cancer cells was sufficient to render cells susceptible to the PARP inhibitors ABT-888 and AZD-2281 both in vitro and in vivo, which was abrogated by HER2 reduction. In addition, ABT-888 significantly inhibited NF-κB (p65/RelA) transcriptional activity in HER2+ but not HER2 negative breast cancer cells. This corresponded with a reduction in phosphorylated p65 and total IKKα levels, with a concomitant increase in IκBα. Overexpression of p65 abrogated cellular sensitivity to ABT-888, whereas IκBα overexpression reduced cell viability to a similar extent as ABT-888. Therefore, susceptibility of HER2+ breast cancer cells to PARP inhibition may be because of inhibition of NF-κB signaling driven by HER2. Our findings indicate that PARP inhibitors may be a novel therapeutic strategy for sporadic HER2+ breast cancer patients. Cancer Res; 72(18); 4796–806. ©2012 AACR.

e15633 Background: In patients (pts) with advanced PSCC receiving first-line chemotherapy (CT), visceral metastases (VM) and ECOG performance status (PS) ≥ 1 were reported to be poor prognostic fac...

606 Background: We have previously found that HER2+ breast cancer cells, despite being DNA repair proficient, are sensitive to poly (ADP-Ribose) polymerase inhibitors (PARPi). In this study, we inv...

476 Background: Kinase inhibitors are the mainstay of therapy for patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC). Since kinases are actionable and lethal metastatic tumor tissue has not been comprehensively studied, we hypothesized that paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may help identify drivers of metastasis and potential therapeutic targets. Methods: Total mRNA isolated from macrodissected formalin fixed paraffin embedded tissue from T, N, and M from 35 pts (total 105 samples) with ccRCC underwent expression profiling for 519 kinase genes using the nCounter System by Nanostring Technologies. Digital raw counts of mRNA abundance were normalized using internal positive and negative controls as well as 7 housekeeping genes. The mean signals from N, T, and M sites were used to calculate change in gene expression, and a p value by t test

389 Background: PSCC is an orphan malignancy with poorly understood biology and suboptimal systemic therapy. Given that kinases may be drivers of disease and readily actionable, we performed comprehensive multiplatform analysis of kinases in PSCC tumor tissue and adjacent normal tissue. Methods: We collected fresh frozen tumors from 10 patients with PSCC, of whom 3 had adjacent normal tissue available. After macrodissection to demarcate tumor from normal tissue, the samples underwent analysis of kinases using platforms to assess DNA, RNA and kinase activity. Next Generation Sequencing of 515 kinase genes was performed using the Agilent Kinome capture and run on the Illumina HiSeq2500 at PE100bp. The Nanostring nCounter platform analyzed the expression (RNA) of 519 kinase genes. Global kinase activity of tissue lysates was measured using Pamstation@12 high-content phospho-peptide substrate microarray system (PamGene International). Upstream kinase prediction was performed and network mapping was done with GeneGo MetaCore. Ingenuity pathway analysis data was performed to integrate over-expression at the activity and gene expression level with coexisting missense mutations at DNA level. Results: Top pathways observed to be upregulated in both the kinase activity and gene expression platforms were PTEN Signaling, STAT3 Pathway, GNRH Signaling, IL8 Signaling and B Cell Receptor Signaling. Potentially relevant missense mutations were seen in 176 kinase genes, with the top altered pathways overlapping with gene overexpression being GNRH Signaling, NF-kB Signaling, and STAT3 pathways. ERBB2, ERBB3 and SYK were altered on gene sequencing and also showed elevated kinase activity. Kinases previously implicated in prostate cancer (PAK4, TNK2), breast cancer (ERBB2) and genital dysplasia (ROR2) also demonstrated mutations. Conclusions: Multiplatform comprehensive analysis of kinases at the DNA, RNA and protein activity levels discovered several potential drivers of PSCC and actionable therapeutic targets. Further validation in preclinical and translational trials is warranted to make advances in this rare malignancy with substantial unmet needs.

Background: Overexpression of HER2 in breast cancer is associated with aggressive tumor features and poor patient survival. Current therapeutic agents targeting this receptor have increased the survival rate of patients with HER2+ breast cancer; however some patients eventually develop resistance to these therapies. We have previously reported that HER2+ breast cancers are susceptible to poly (ADP-Ribose) polymerase inhibitors (PARPi) alone independent of a basal or induced DNA repair deficiency but instead via suppression of NF-κB signaling. In this study, we investigated PARPi sensitivity in HER2+ breast cancer cells that are resistant to the HER2 targeted agent trastuzumab. Materials and Methods: HER2+ breast cancer cell lines BT-474, UACC812, SKBRR3 and their trastuzumab resistant counterparts were used in this study. Cells were treated with vehicle or 10µM ABT-888 or transfected with scrambled or PARP1 siRNA. NF-κB transcriptional activity was measured using a NF-κB-driven luciferase reporter assay. Protein expression was measured by Western blot analysis. Cellular cytotoxicity and viability following PARPi was assessed with colony formation and ATPlite assays, respectively. Results: HER2+ parent and trastuzumab resistant breast cancer cells showed similar susceptibility to the PARPi ABT-888. There was a dose response reduction in survival fraction (greater than 70% at 10μM) and a greater than 40% decrease in cell viability with 10μM ABT-888. This cytotoxicity was associated with more than 50% attenuation of NF-κB transcriptional activity and reduced expression of the NF-κB activator IKKα. Suppression of NF-κB signaling was also observed utilizing PARP1 siRNA. Conclusions: HER2+ breast cancer cells resistant to trastuzumab continue to be sensitive to PARP inhibition through attenuation of the NF-κB signaling pathway. These results support the use of PARPi as part of a therapeutic strategy for patients with HER2+ breast cancer. Citation Format: Monica E. Wielgos, Tiffiny Cooper, Andres Forero, James A. Bonner, Francisco J. Esteva, C K. Osborne, Rachel Schiff, Albert F. LoBuglio, Eddy S. Yang. Trastuzumab resistant HER2+ breast cancer cells retain sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. [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 5469. doi:10.1158/1538-7445.AM2014-5469

Background/Objectives: Few therapeutic options are effective for triple negative breast cancers (TNBCs) necessitating novel approaches. We previously reported a novel synthetic lethality with combined EGFR and PARP inhibition due to a homologous recombination (HR) repair defect induced EGFR inhibition. The mechanism of the HR deficiency involved disruption of EGFR/BRCA1 interaction and sequestration of EGFR and BRCA1 to the cytosol. In this study, we have extended these findings to encompass multiple subtypes of triple negative breast cancer and EGFR inhibitors. Additionally, we further investigated the mechanisms by which EGFR regulates HR DNA repair. Methods: TNBC cells, including MDA-MB-231 (mesenchymal stem-like), MDA-MB-468 (basal-like), HCC1187 (immunomodulatory), BT549 (mesenchymal), MDA-MB-453 (luminal androgen receptor), were assessed for cytotoxicity and cell viability following EGFR inhibition (lapatinib, erlotinib, or cetuximab), PARP inhibition, or both by colony formation or ATPlite assays. MALDI-TOF mass spectroscopy was utilized to ascertain protein-protein interaction. To confirm interaction data and determine subcellular location we utilized immunoprecipitation and subcellular fractionation. To determine if interactions were dependent on DNA, lysates were treated with Ethidium Bromide and DNAse prior to immunoprecipitation. Results: EGFR inhibition with lapatinib, cetuximab, or erlotinib induced a contextual synthetic lethality with the PARP inhibitor, veliparib, in vitro in multiple TNBC subtypes, including MDA-MB-231 (mesenchymal stem-like), MDA-MB-468 (basal-like), HCC1187 (immunomodulatory), BT549 (mesenchymal), MDA-MB-453 (luminal androgen receptor). Interestingly, mass spectroscopy reaffirmed EGFR interaction with BRCA1 but also identified a novel interaction between EGFR and PARP1. These interactions were not found upon EGFR inhibition with lapatinib. Furthermore, we validated with immunoprecipitation and in vitro protein binding assays EGFR, BRCA1, and PARP1 protein-protein interactions that were disrupted upon EGFR inhibition. Additionally, these proteins were found to interact in the nucleus, independent of DNA. Lastly, EGFR inhibition also reduced nuclear EGFR and BRCA1 without significant changes in PARP1 localization. Conclusions: These results reveal a contextual synthetic lethality between combined EGFR and PARP inhibition in multiple subtypes of TNBC, suggesting potential generalizability of this combination in patients with TNBC. Furthermore understanding the mechanism by which EGFR regulates DNA repair may provide novel targets to confer other contextual synthetic lethalities that may be exploited to treat the aggressive TNBCs. Citation Format: Jennifer Anne Stanley, Somaira Nowsheen, Tiffiny Cooper, Andres Forero, Alfred LoBuglio, Eddy Yang. Contextual synthetic lethality in human triple negative breast cancer cells involving a novel interaction between DNA repair proteins EGFR, PARP1, and BRCA1. [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 5471. doi:10.1158/1538-7445.AM2014-5471

70 Background: Dysregulation of the HER/EGFR family is identified in esophageal cancers and confers resistance and inferior survival rates. In addition to their unique selectivity in killing DNA repair-deficient tumors, poly-ADP ribose polymerase inhibitors (PARPi) can enhance radiation-induced cytotoxicity. We and others have also previously demonstrated attenuation of DNA repair capacity in HER-inhibited cells to induce a contextual synthetic lethal interaction with PARPi. We thus hypothesized that erlotinib, a tyrosine kinase inhibitor directed against HER1/HER2, could induce a transient DNA repair deficit and subsequently increase DNA damage with the PARPi veliparib in esophageal cancer cells while increasing tumor radiation (RT) sensitivity. Methods: Esophageal SCC cell lines (KYSE-30, KYSE-410, and OE-21) were treated with combinations of vehicle, erlotinib, veliparib (a PARP1/2 inhibitor), and RT. DNA damage and repair and signaling proteins were assessed by immunofluorescence staining of cells for DNA damage and repair foci and/or western blot analysis. Cell viability and cytotoxicity were determined via cell proliferation assays and colony formation assays, respectively. Tumor growth delay was assessed in mice bearing esophageal tumor xenografts. Results: Consistent with our hypotheses, erlotinib increased γ-H2AX foci, a marker of DNA double strand breaks (DSBs), in all three esophageal SCC tumor cells. This coincided with reduced DSB-repair capacity as assessed via RAD51 foci and pDNA-PK. Triple combination with erlotinib, veliparib, and RT demonstrated enhanced cytotoxicity. A subsequent increase in Annexin positive cells was observed, indicative of activation of the apoptotic response. Importantly, the triple combination was most effective in suppressing the growth of esophageal tumor xenografts in vivo (2– to 5.5–fold lower tumor volume) relative to other treatment groups. Furthermore, we observed reductions in tumor volume from baseline with this triple combination in 3/6 mice. Conclusions: Thus, the combination of erlotinib, PARPi, and RT can be an innovative and effective treatment strategy to enhance the therapeutic ratio and improve outcomes in esophageal SCC cancer patients.

Purpose: The human papilloma virus (HPV) has recently become a prevalent cause of human head and neck cancer (HNC), which often exhibits dysregulated epidermal growth factor receptor (EGFR) signaling. We previously reported that in non-HPV-associated HNC, inhibition of EGFR (EGFRi) attenuates DNA double stranded break (DSB) repair and subsequently sensitizes tumors to inhibitors of poly (ADP-ribose) polymerase (PARP), which target DNA repair deficient tumors. Because patients with HPV-associated HNC have been shown to exhibit increased sensitivity to DNA damage, we evaluated the response of HPV (+) HNC cells to combination EGFRi and PARPi compared to HPV (-) HNC cells. Methods: HPV (-) UM-SCC1 and UM-SCC6, as well as HPV (+) SCC-47 and SCC-90 were utilized for in vitro studies. Cell growth and survival fraction were evaluated via cell proliferation and colony formation assays, respectively. DNA damage studies were performed using standard γ-H2AX and Rad51 foci. Lastly, in vivo studies were conducted in mice bearing HNC tumor xenografts as well as a human tumor explant from a lymph node metastasis of a HPV(+) HNC patient. Results: Interestingly, HPV (+) HNCs exhibited the greatest sensitivity both in vitro and in vivo to PARP inhibition alone. This correlated with a blunted DNA damage response. In contrast, HPV (-) HNCs were most sensitive to combination EGFRi/PARPi, which correlated with persistent DNA damage. Conclusions: HPV(+) head and neck cancers may be sensitive to PARP inhibition alone. Our in vitro and in vivo results warrant further testing of PARP inhibitors as part of therapy for HNCs. Citation Format: Tiffiny Cooper, Marcela Rodriguez, Hoa Q. Trummell, Alice Weaver, James A. Bonner, Eddy S. Yang. PARP inhibition in HPV positive head and neck cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 635. doi:10.1158/1538-7445.AM2013-635

621 Background: HER2 overexpression in breast cancer confers increased tumor aggressiveness. Targeted therapy against HER2 has improved outcomes, but resistance and disease progression ultimately occurs, thus necessitating novel therapeutic strategies. PARP inhibitors target homologous recombination (HR) deficient tumors, such as the BRCA-associated breast and ovarian cancers. In this study, we report unexpected susceptibility of HER2+ breast cancer cells to PARP inhibition alone independent of an inherent HR deficiency. Methods: Cell viability was measured using colony formation and ATPLite assays. Tumor growth delay was assessed in vivo in mice bearing breast cancer xenografts. Proteins were detected by immunoblotting. HR was assayed using radiation (IR)-induced Rad51 foci or a GFP-based HR assay. NFκB activity was measured using a NFκB-driven luciferase assay. Results: Surprisingly, PARP inhibition with ABT-888 alone reduced the colony forming ability and cell viability of the HER2+ breast cancer cell lines BT474, SKBR3, MDA-MB361, and HCC1954 (~70 – 99% reduction at 10μM). This susceptibility did not correlate with an inherent HR deficit. Interestingly, HER2 overexpression itself may be one mechanism of susceptibility to ABT-888 as evidenced by increased cellular cytotoxicity and in vivo tumor growth delay of MCF7 cells stably expressing HER2. Further dissection of the mechanism revealed that NFκB transcriptional activity was significantly inhibited by ABT-888 (>95%) which corresponded with reduced levels of phosphorylated p65 and total IKKα, and a concomitant increase in IkBα. Furthermore, overexpression of p65 abrogated cellular sensitivity to ABT-888. Conclusions: HER2+ breast cancer cells are highly susceptible to PARP inhibition despite being HR proficient. This may be, in part, due to inhibition of NFκB. Further investigation of whether the addition of PARP inhibition to HER2 targeted therapy will delay the onset of resistance to therapy is warranted to potentially improve outcomes in HER2+ breast cancer patients.

Purpose: Dysregulation of the epidermal growth factor receptor (EGFR) family is a hallmark of many cancers. Although targeting of EGFR family has improved outcomes, many patients ultimately fail this therapy. PARP inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing homologous recombination (HR)-deficient tumors while maintaining minimal toxicity in normal tissues. We have previously shown that EGFR inhibition induces synthetic lethality with PARPi in head and neck squamous cell carcinomas (HNSCCs) in vitro by attenuating DNA repair pathways. In this study, we validated these observations in vivo in HNSCCs xenografts. Importantly, we also tested this strategy in other EGFR dysregulated cancers. Methods: Cervical, breast, and head and neck cancer cell lines were used in this study. DNA damage and repair were assessed by immunofluorescence staining of cells for γ-H2AX, Rad51, and DNA-Pk foci and/or chromosomally integrated HR and nonhomologous end-joining based GFP reporter assays. Cell viability was determined via colony formation and ATPlite assays. Tumor growth delay was assessed in mice bearing tumor xenografts. Results: Combined EGFR and PARP inhibition resulted in the greatest tumor growth delay versus either agent alone in mice bearing head and neck tumor xenografts (9 week tumor growth delay when compared to PARPi alone, 3 week tumor growth delay when compared to EGFR inhibitor alone). This correlated with persistent γ-H2AX foci indicative of unresolved DNA damage. Interestingly, this combination was also effective in other EGFR dysregulated tumors. Human cervical and breast cancer cells exhibited enhanced cytotoxicity with EGFR and PARP inhibition compared to either agent alone (80-99% cytotoxicity with combination vs 0-20% with either agent alone). Similar to head and neck cancer, susceptibility to PARPi induced by EGFR inhibition was associated with deficient NHEJ- and HR-mediated DNA repair and subsequent persistence of DNA damage. Conclusions: Thus, by generating a DNA repair deficit, EGFR inhibition can induce synthetic lethality with PARP inhibition. This can be an innovative treatment strategy for tumors with dysregulated EGFR signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4684. doi:1538-7445.AM2012-4684