Lorna Pope

First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors

PURPOSE AKT signaling is frequently deregulated in human cancers. MK-2206 is a potent, oral allosteric inhibitor of all AKT isoforms with antitumor activity in preclinical models. A phase I study of MK-2206 was conducted to investigate its safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics (PDs), and preliminary antitumor efficacy. PATIENTS AND METHODS Patients with advanced solid tumors received MK-2206 on alternate days. Paired tumor biopsies were mandated at the MTD for biomarker studies. PD studies incorporated tumor and hair follicle analyses, and putative predictive biomarker studies included tumor somatic mutation analyses and immunohistochemistry for phosphatase and tensin homolog (PTEN) loss. RESULTS Thirty-three patients received MK-2206 at 30, 60, 75, or 90 mg on alternate days. Dose-limiting toxicities included skin rash and stomatitis, establishing the MTD at 60 mg. Drug-related toxicities included skin rash (51.5%), nausea (36.4%), pruritus (24.2%), hyperglycemia (21.2%), and diarrhea (21.2%). PKs (area under the concentration-time curve from 0 to 48 hours and maximum measured plasma concentration) were dose proportional. Phosphorylated serine 473 AKT declined in all tumor biopsies assessed (P = .015), and phosphorylated threonine 246 proline-rich AKT substrate 40 was suppressed in hair follicles at 6 hours (P = .008), on days 7 (P = .028) and 15 (P = .025) with MK-2206; reversible hyperglycemia and increases in insulin c-peptide were also observed, confirming target modulation. A patient with pancreatic adenocarcinoma (PTEN loss; KRAS G12D mutation) treated at 60 mg on alternate days experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. Two patients with pancreatic neuroendocrine tumors had minor tumor responses. CONCLUSION MK-2206 was well tolerated, with evidence of AKT signaling blockade. Rational combination trials are ongoing to maximize clinical benefit with this therapeutic strategy.

Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies

PURPOSE The hepatocyte growth factor/c-MET axis is implicated in tumor cell proliferation, survival, and angiogenesis. ARQ 197 is an oral, selective, non-adenosine triphosphate competitive c-MET inhibitor. A phase I trial of ARQ 197 was conducted to assess safety, tolerability, and target inhibition, including intratumoral c-MET signaling, apoptosis, and angiogenesis. PATIENTS AND METHODS Patients with solid tumors amenable to pharmacokinetic and pharmacodynamic studies using serial biopsies, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and circulating endothelial cell (CEC) and circulating tumor cell (CTC) enumeration were enrolled. RESULTS Fifty-one patients received ARQ 197 at 100 to 400 mg twice per day. ARQ 197 was well tolerated, with the most common toxicities being grade 1 to 2 fatigue, nausea, and vomiting. Dose-limiting toxicities included grade 3 fatigue (200 mg twice per day; n = 1); grade 3 mucositis, palmar-plantar erythrodysesthesia, and hypokalemia (400 mg twice per day; n = 1); and grade 3 to 4 febrile neutropenia (400 mg twice per day, n = 2; 360 mg twice per day, n = 1). The recommended phase II dose was 360 mg twice per day. ARQ 197 systemic exposure was dose dependent and supported twice per day oral dosing. ARQ 197 decreased phosphorylated c-MET, total c-MET, and phosphorylated focal adhesion kinase and increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) staining in tumor biopsies (n = 15). CECs decreased in 25 (58.1%) of 43 patients, but no significant changes in DCE-MRI parameters were observed after ARQ 197 treatment. Of 15 patients with detectable CTCs, eight (53.3%) had ≥ 30% decline in CTCs after treatment. Stable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), ≥ 4 months was observed in 14 patients, with minor regressions in gastric and Merkel cell cancers. CONCLUSION ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non-small-cell lung cancer, is ongoing.

Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers.

Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5–1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical ‘hot-spot’ mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid biomarker studies have clinically important multi-purpose utility in advanced cancer patients and further studies to pursue their incorporation into the standard of care are warranted.

The Association of PI3 Kinase Signaling and Chemoresistance in Advanced Ovarian Cancer

Evidence that the phosphoinositide 3-kinase (PI3K) pathway is deregulated in ovarian cancer is largely based on the analysis of surgical specimens sampled at diagnosis and may not reflect the biology of advanced ovarian cancer. We aimed to investigate PI3K signaling in cancer cells isolated from patients with advanced ovarian cancer. Ascites samples were analyzed from 88 patients, of whom 61 received further treatment. Cancer cells were immunomagnetically separated from ascites, and the signaling output of the PI3K pathway was studied by quantifying p-AKT, p-p70S6K, and p-GSK3β by ELISA. Relevant oncogenes, such as PIK3CA and AKT, were sequenced by PCR-amplified mass spectroscopy detection methods. In addition, PIK3CA and AKT2 amplifications and PTEN deletions were analyzed by FISH. p-p70S6K levels were significantly higher in cells from 37 of 61 patients who did not respond to subsequent chemotherapy (0.7184 vs. 0.3496; P = 0.0100), and this difference was greater in patients who had not received previous chemotherapy. PIK3CA and AKT mutations were present in 5% and 0% of samples, respectively. Amplification of PIK3CA and AKT2 and deletion of PTEN was seen in 10%, 10%, and 27% of samples, respectively. Mutations of PIK3CA and amplification of PIK3CA/AKT2 or deletion of PTEN did not correlate with levels of p-AKT, p-p70S6K, and p-GSK3β. In patients with advanced ovarian cancer, there is an association between levels of p-p70S6K and response to subsequent chemotherapy. There is no clear evidence that this is driven specifically by PIK3CA or AKT mutations or by amplifications or deletion of PTEN. Mol Cancer Ther; 11(7); 1609–17. ©2012 AACR.

Baseline Circulating Tumor Cell Counts Significantly Enhance a Prognostic Score for Patients Participating in Phase I Oncology Trials

Background: High circulating tumor cell (CTC) counts are associated with poor prognosis in several cancers. Enrollment of patients on phase I oncology trials requires a careful assessment of the potential risks and benefits. Many patients enrolled on such trials using established eligibility criteria have a short life expectancy and are less likely to benefit from trial participation. We hypothesized that the incorporation of CTC counts might improve patient selection for phase I trials. Methods: This retrospective analysis evaluated patients who had baseline CTCs enumerated prior to their starting on a phase I trial. CTCs were enumerated using the CellSearch System. Results: Between January 2006 and December 2009 a total of 128 patients enrolled in phase I trials had CTC counts evaluated. Higher CTC counts as a continuous variable independently correlated with risk of death in this patient population (P = 0.006). A multivariate point-based risk model was generated using CTCs as a dichotomous variable (≥3 or <3), and incorporated other established prognostic factors, including albumin <35 g/L, lactate dehydrogenase greater than upper limit of normal, and >2 metastatic sites. Comparison of receiver operating characteristic curves demonstrated that the addition of baseline CTC counts improved the performance of the prospectively validated Royal Marsden Hospital phase I prognostic score, which now identifies three risk groups (P < 0.0001): good prognosis [score 0–1, median overall survival (OS) 63.7 weeks], intermediate prognosis (score 2–3, median OS 37.3 weeks), and poor prognosis (score 4, median OS 13.4 weeks). Conclusion: CTC enumeration improved the performance of a validated prognostic score to help select patients for phase I oncology trials. Clin Cancer Res; 17(15); 5188–96. ©2011 AACR.

First-in-Human Study of CH5132799, an Oral Class I PI3K Inhibitor, Studying Toxicity, Pharmacokinetics, and Pharmacodynamics, in Patients with Metastatic Cancer

Purpose: This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of CH5132799. Experimental Design: Patients with metastatic solid tumors were eligible for the study. CH5132799 was administered orally once daily or twice daily in 28-day cycles. Results: Thirty-eight patients with solid tumors received CH5132799 at 2 to 96 mg once daily or 48 to 72 mg twice daily. The MTD was 48 mg on the twice-daily schedule but was not reached on the once daily schedule. DLTs were grade 3 elevated liver function tests (LFT), grade 3 fatigue, grade 3 encephalopathy, grade 3 diarrhea, and grade 3 diarrhea with grade 3 stomatitis; all DLTs were reversible. Most drug-related adverse events were grade 1/2. Diarrhea (34%) and nausea (32%) were the most common events. Mean Cmax and AUC0-24 in steady state at MTD were 175 ng/mL and 1,550 ng·h/mL, respectively, consistent with efficacious exposure based on preclinical modeling. Reduction in SUVmax with [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) was observed in 5 of 7 patients at MTD. A patient with PIK3CA-mutated clear cell carcinoma of the ovary achieved a partial response by GCIG CA125 criteria and further, a heavily pretreated patient with triple-negative breast cancer had marked improvement in her cutaneous skin lesions lasting six cycles. Conclusion: CH5132799 is well tolerated at the MTD dose of 48 mg twice daily. At this dose, the drug had a favorable PK and PD profile and preliminary evidence of clinical activity. Clin Cancer Res; 20(23); 5908–17. ©2014 AACR.

Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)

Background Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. Objective To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. Design, setting, and participants Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75 mg/m2) or cabazitaxel (20 or 25 mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25 mg/m2) as second-line chemotherapy (PROSELICA). Outcome measurements and statistical analysis Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. Results and limitations In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR] = 1.54; 95% confidence interval [CI]: 1.15–2.08; p = 0.004), and shorter OS on taxane therapy (HR = 1.53; 95% CI: 1.18–1.97; p = 0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle −0.03; 95% CI: −0.044 to −0.009; p = 0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. Conclusions We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. Patient summary In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cfDNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cfDNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cfDNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cfDNA concentration during the first 3–9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cfDNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cfDNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA.

Abstract A067: Targeting the bromodomain and extra-terminal (BET) family proteins and beyond in metastatic castration-resistant prostate cancer (mCRPC): Overcoming aberrant androgen receptor (AR) signaling

Despite robust responses to androgen deprivation therapy and AR targeting therapies (including abiraterone and enzalutamide), nearly all cases of advanced prostate cancer progress to lethal mCRPC and develop therapeutic resistance. This progression is associated with persistent AR signaling, in part due to expression of constitutively active AR splice variants that include AR variant 7 (AR-V7). We show that AR-V7 expression in patient biopsies (protein) and circulating tumor cells (RNA) associates with poor outcome from mCRPC. Therapies that regulate AR-V7 and induce robust anticancer responses are required to confirm the clinical importance of AR-V7 in mCRPC. One such promising approach, currently in clinical trials, is inhibitors of BET family proteins, which include BRD2, BRD3, and BRD4. Preclinical studies have shown that BRD4 binds to AR at the androgen response element and facilitates the recruitment of the transcriptional machinery. We show that BRD4 protein expression increases as patients develop mCRPC and at diagnosis associates with patient outcome and more advanced disease. In addition, through RNAseq analysis we show that expression levels of BRD2, 3, and 4 in mCRPC associated with degree of AR activity. We, and others, have shown that the use of BET inhibitors (BETi) in vitro on AR/AR-V7 expressing cell lines not only decreased AR activity but also preferentially decreased the production on AR-V7 mRNA. In light of BETi having efficacy against BRD2, 3, and 4, and all isoforms being expressed in mCRPC, we explored the effect of genetic knockdown of each isoform. We show that BETi treatment is sufficient to decrease AR-V7 mRNA and protein in CRPC cell lines. Moreover, we demonstrate that BRD4 knockdown, and to a greater extent, the combination of BRD2, 3, and 4 knockdown blocked AR and AR-V7 signaling. Furthermore, C-MYC knockdown did not recapitulate the effect of BETi and led to an increase in AR signaling. Consistent with these findings, BETi and the combination of BRD2, 3, and 4 knockdown reduced the growth of CRPC cell lines. To further investigate whether BETi is sufficient to inhibit AR-V7 production in patients with mCRPC, we treated patient-derived organoids (PDOs) and a mouse xenograft (PDX) grown from patient metastatic biopsies who had progressed on enzalutamide and/or abiraterone. In this study 4 out of 9 PDOs were sensitive to BETi. Consistent with cell culture experiments, BETi treatment of PDO and PDX led to downregulation of both AR-V7 mRNA and protein expression, and growth inhibition. In light of the pleotropic effects of BETi on cancer cell biology and potential for treatment-related toxicities, we explored whether we could identify critical factors for BETi mediated AR-V7 regulation in CRPC. The ability of BETi to regulate AR-V7 may suggest an effect of BETi on pre-mRNA splicing of AR resulting in the observed decrease of AR-V7 expression. RNAseq analysis of the AR-V7 expressing CRPC cell line LNCaP95 treated with BETi demonstrated an increase in total splicing. Despite this, focused analysis of splicing factors and spliceosome components identified a subset of eight splicing factors being downregulated by BETi treatment, including one yet-uncharacterized factor (splicing factor B; Sf-B) that is crucial for AR-V7 expression and LNCaP95 cell growth. In addition, mCRPC patients who express high levels of Sf-B had a significantly poorer outcome and the protein structure of Sf-B is druggable using the drug discovery knowledgebase canSAR. Based on our results, we propose that inhibition of Sf-B may lead to decreased splicing and expression of AR-V7; providing a novel approach to target AR-V7 in mCRPC. Citation Format: Adam Sharp, Jon Welti, Wei Yuan, Ines Figueiredo, Veronica Gil, Daniel Nava Rodrigues, Maryou Lambros, Eleanor Knight, Jian Ning, Jeff Francis, David Dolling, Lorna Pope, Antje Neeb, Gunther Boysen, Yezi Zhu, Mateus Crespo, Alec Paschalis, Jun Luo, Stephen Plymate, Bissan Al-Lazikani, Amanda Swain, Johann de Bono. Targeting the bromodomain and extra-terminal (BET) family proteins and beyond in metastatic castration-resistant prostate cancer (mCRPC): Overcoming aberrant androgen receptor (AR) signaling [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A067.

Prospective study of genetic mutations in matched tumor and plasma specimens in colorectal cancer patients.

356 Background: Circulating free DNA (cfDNA) represents a minimally-invasive resource for detecting mutations in advanced cancer patients. The primary objective of this study was to determine if cfDNA is representative of tumor tissue for multiplex mutation detection utilizing Sequenom MassARRAY. METHODS Samples were spiked with dilutions (10ng/μl to 0.01ng/μl) of HCT116 DNA containing KRAS G13D mutations to determine assay sensitivity and specificity. Metastatic colorectal cancer patients referred to the Drug Development Unit at the Royal Marsden Hospital between 9/09-8/10 gave their consent to provide DNA from matched archival formalin fixed paraffin-embedded (FFPE) tumor and plasma. Samples had ∼200 described gene mutations genotyped using Sequenom MassARRAY (OncoCarta Panel). RESULTS Serial dilution spiking experiments revealed that the KRAS G13D mutation was reproducibly detectable to 40ng/mL of HCT116 DNA; 26 patient samples were then analyzed. KRAS, BRAF and PIK3CA mutations were detected in 8 (31%), 3 (12%) and 3 (12%) tumor specimens respectively; 100% concordance for KRAS status was observed between multiple FFPE biopsies from the same patient and analysis by Amplification Refractory Mutation System (ARMS)-Scorpion PCR. The median quantity of cfDNA was 353ng/ml (range 106-4603). Concordance between matched FFPE and cfDNA was 88% for KRAS and 100% for BRAF mutations. No patients with wildtype KRAS or BRAF tumor genotypes had mutations in their respective cfDNA confirming the high specificity of cfDNA analysis. Three patients had detectable PIK3CA mutations; 1 patient had a E346K mutation detected in both FFPE tissue and plasma; 1 patient had E545K detected only in FFPE and the other had E542K detected in a liver metastasis but not in the colorectal primary or plasma. The recently reported oncogenic AKT1 E17K mutation was detected in 1 patient in tissue and plasma. No mutations in any of the other tested oncogenes studied were detected. CONCLUSIONS A high concordance in detected mutations was observed between FFPE tumor and matched cfDNA. cfDNA is representative of tumor DNA and may be used for the prospective selection of cancer patients for treatment with targeted therapeutics. No significant financial relationships to disclose.

Abstract 3072: Prospective study of genetic mutations in matched tumor and plasma specimens in advanced cancer patients referred to phase I trials

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Circulating free DNA (cfDNA) represents a minimally-invasive resource for detecting mutations in advanced cancer patients. The primary objective of this study was to determine if cfDNA is representative of tumor tissue for multiplex mutation detection utilizing Sequenom MassARRAY. Methods: Metastatic colorectal, breast, melanoma and ovary cancer patients referred to the Drug Development Unit at the Royal Marsden Hospital between 9/09-8/10 gave their consent to provide DNA from matched archival formalin fixed paraffin embedded (FFPE) tumor and plasma. Samples mutation genotyping using the Sequenom MassARRAY technology and the OncoCartaTM Panel allowed the parallel analysis of 238 simple and complex mutations across 19 selected key oncogenes. Dilutions (10ng/µl to 0.01ng/µl) of HCT116 DNA containing KRAS G13D mutation were used to determine assay sensitivity and specificity. Results: Serial dilution spiking experiments revealed that the KRAS G13D mutation was reproducibly detectable to 40ng/ml of HCT116 DNA; 74 patient samples were then analyzed. The median quantity of cfDNA was 305ng/ml (range 10-32000). Of the 25 colorectal patients, the median quantity of cfDNA was 361ng/ml (range 189-4603); KRAS, BRAF and PIK3CA mutations were detected in 8 (31%), 3 (12%) and 3 (12%) tumor specimens respectively; concordant data for matched plasma tumor DNA was found in 88% of patients for KRAS, 100% for BRAF mutations and 33% for PIK3CA (1 patient had a PIK3CA mutation in primary and plasma; one patient had a mutation detected only in the primary; one patient had no mutation in the primary or plasma, but a mutation detected in a metastatic liver deposit). The recently reported oncogenic AKT1 E17K mutation was detected in 1 colorectal patient in tissue and plasma. Of the 19 breast cancer patients, the median cfDNA concentration was 354ng/ml (range 10-32000); PIK3CA H1047R mutation was detected in 4 (21%) FFPE tumor specimens; concordance between matched FFPE and cfDNA was 75% (3 out of 4 patients). The AKT1 E17K mutation was detected in 1 patient in both tissue and plasma. In 15 melanoma patients the median cfDNA concentration was 141ng/ml (range 46-1002); BRAF V600E, NRAS codon 61 and MET R970C mutations were detected in 4 (27%), 3 (20%) and 1 (7%) FFPE tumor specimens respectively. Concordance between matched FFPE and cfDNA was 50% for BRAF, 75% for NRAS and 100% for MET mutations. Another MET mutation, T992I, was found in plasma but not in tissue for one patient. Of the 15 ovary patients, the median cfDNA concentration was 261ng/ml (range 79-957). Two KRAS mutations and 1 PIK3CA H1047R mutation were detected in FFPE, but no mutation was found in any plasma sample. Conclusions: A high concordance in detected mutations was observed between FFPE tumor and matched cfDNA. cfDNA is representative of tumor DNA and may be used for the prospective selection of cancer patients for targeted therapy. 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 3072. doi:10.1158/1538-7445.AM2011-3072