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Supplementary Table 1 from Ovarian Cancer Stem Cell–Like Side Populations Are Enriched Following Chemotherapy and Overexpress EZH2

PDF file, 47KB, Reproducibility of immunomagnetic separation and ELISA.

Supplementary Table 2 from Ovarian Cancer Stem Cell–Like Side Populations Are Enriched Following Chemotherapy and Overexpress EZH2

PDF file, 80KB, Experiments detailing the validation of immunomagnetic separation and ELISA.

PDF file, 63KB.

PDF file, 66KB, Oncogenes and mutations detected using the OncoCarta Panel v1.0.

Platinum-based chemotherapy, with cytoreductive surgery, is the cornerstone of treatment of advanced ovarian cancer; however, acquired drug resistance is a major clinical obstacle. It has been proposed that subpopulations of tumor cells with stem cell–like properties, such as so-called side populations (SP) that overexpress ABC drug transporters, can sustain the growth of drug-resistant tumor cells, leading to tumor recurrence following chemotherapy. The histone methyltransferase EZH2 is a key component of the polycomb-repressive complex 2 required for maintenance of a stem cell state, and overexpression has been implicated in drug resistance and shorter survival of ovarian cancer patients. We observed higher percentage SP in ascites from patients that have relapsed following chemotherapy compared with chemonaive patients, consistent with selection for this subpopulation during platinum-based chemotherapy. Furthermore, ABCB1 (P-glycoprotein) and EZH2 are consistently overexpressed in SP compared with non-SP from patients' tumor cells. The siRNA knockdown of EZH2 leads to loss of SP in ovarian tumor models, reduced anchorage-independent growth, and reduced tumor growth in vivo. Together, these data support a key role for EZH2 in the maintenance of a drug-resistant, tumor-sustaining subpopulation of cells in ovarian cancers undergoing chemotherapy. As such, EZH2 is an important target for anticancer drug development. Mol Cancer Ther; 10(2); 325–35. ©2010 AACR.

PDF file, 63KB, Survival based on signalling output in total population of 88 patients.

PDF file, 71KB, Efficiency of immunomagnetic separation.

PDF file, 44KB, Probes for PIK3CA, AKT2 and PTEN.

Supplementary Figure 1: 79 patients enrolled in study.

Purpose: We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors.Experimental Design: This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1–3 every 14 days; S2, days 1–5 every 14 days; S3, days 1–7 every 14 days]. A fed-fasting expansion cohort was included in the study.Results: Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3–4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1–2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses.Conclusion: The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 693–700. ©2014 AACR.See related commentary by Yee, p. 667

Supplementary Materials Table 1. Ratio of area under the curve during the time interval between consecutive dosing (AUCtau) on day 3 to AUCtau on day 1 (schedule 1 [S1]) Table 2. Ratio of area under the curve during the time interval between consecutive dosing (AUCtau) on day 5 (S2) or day 7 (S3) to AUCtau on day 1.

Supplementary Figures 1-3 from Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer

Supplementary Figure Legends 1-5 from Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer

Supplementary Tables 5-8 from Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer

Supplementary Figure 4 from Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer

Supplementary Figure 5 from Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer

Supplementary Tables 1-4 from Characterization of ERG, AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer

Purpose: We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors. Experimental Design: This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1–3 every 14 days; S2, days 1–5 every 14 days; S3, days 1–7 every 14 days]. A fed-fasting expansion cohort was included in the study. Results: Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3–4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1–2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses. Conclusion: The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 693–700. ©2014 AACR. See related commentary by Yee, p. 667

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.

Platinum-based chemotherapy, with cytoreductive surgery, is the cornerstone of treatment of advanced ovarian cancer; however, acquired drug resistance is a major clinical obstacle. It has been proposed that subpopulations of tumor cells with stem cell–like properties, such as so-called side populations (SP) that overexpress ABC drug transporters, can sustain the growth of drug-resistant tumor cells, leading to tumor recurrence following chemotherapy. The histone methyltransferase EZH2 is a key component of the polycomb-repressive complex 2 required for maintenance of a stem cell state, and overexpression has been implicated in drug resistance and shorter survival of ovarian cancer patients. We observed higher percentage SP in ascites from patients that have relapsed following chemotherapy compared with chemonaive patients, consistent with selection for this subpopulation during platinum-based chemotherapy. Furthermore, ABCB1 (P-glycoprotein) and EZH2 are consistently overexpressed in SP compared with non-SP from patients' tumor cells. The siRNA knockdown of EZH2 leads to loss of SP in ovarian tumor models, reduced anchorage-independent growth, and reduced tumor growth in vivo. Together, these data support a key role for EZH2 in the maintenance of a drug-resistant, tumor-sustaining subpopulation of cells in ovarian cancers undergoing chemotherapy. As such, EZH2 is an important target for anticancer drug development. Mol Cancer Ther; 10(2); 325–35. ©2010 AACR.

BackgroundPrevious studies investigating the effect of increased dose intensity and chemotherapy-induced neutropenia in patients with advanced non-small cell lung cancer (NSCLC) have not consistently shown significant survival benefits.MethodsThis retrospective analysis reviewed the outcome of patients receiving palliative chemotherapy for advanced NSCLC (stages III–IV) at the Royal Marsden Hospital. Regimens included cisplatin or carboplatin with either vinorelbine or gemcitabine on days 1 and 8, every 21 days. Patients who received at least four cycles of chemotherapy were classified into groups based on dose intensity, dose reductions, and worst grade of neutropenia for a landmark analysis. Comparisons between these groups for time to progression and overall survival were made by standard univariate and multivariate methods.ResultsOne hundred sixty-nine of a total of 190 patients who received more than four cycles of chemotherapy during the period between November 1998 and December 2008 were included. One hundred twenty-five (73.9%) patients received four chemotherapy cycles with the remaining receiving up to six cycles. The median relative dose intensity for platinum was 93.9% (62.1–102%) and for vinorelbine/gemcitabine was 91.7% (37.8–105%). Dose reductions were recorded in 64 patients (37.8%), and 65 patients (38.5%) had grades 3 to 4 neutropenia. There were no statistically significant differences in time to progression and overall survival between any of the subgroups.ConclusionsThis retrospective analysis demonstrates no significant relationship between survival and dose intensity (

Topotecan, a topoisomerase 1 inhibitor (topo1-i), is a semi-synthetic derivative of camptothecan with well-established cytotoxic properties. It is licensed for the treatment of relapsed, sensitive small cell lung cancer (SCLC) and for second line treatment in ovarian cancer. Studies have also shown this drug to be an effective first line treatment for SCLC with either cisplatin or in combination with a topoisomerase 2 inhibitor (topo2-i), etoposide; both combinations have shown similar efficacy. Oral and parenteral formulations of topotecan have proven to be equivocal in relapsed SCLC patients. The parenteral form showed reduced rates of severe haematological toxicities and better symptom control than an anthracycline combination (CAV). In relapsed SCLC, a randomised phase III trial of oral topotecan versus best supportive care showed a statistically significant increase in overall survival. In the second line treatment of non-small cell lung cancer (NSCLC), oral topotecan was not inferior to the current standard iv docetaxel for 1 year survival rates. Worthwhile potential investigations include combining oral topotecan with other oral agents to design treatments for different lines of therapy. The new oral formulation of topotecan also lends itself to testing with small molecule tyrosine kinase inhibitors. The myelosuppressive toxicity profile needs to be vigorously monitored and managed. The trials with oral topotecan have also highlighted the need to reassess the utility of the terms ‘sensitive’ and ‘resistant’ in the selection of patients with relapsed small cell lung cancer.

Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC) by anti–epithelial cell adhesion molecule immunomagnetic selection followed by cytokeratin and CD45 immunofluorescence and 4′,6-diamidino-2-phenylindole staining. We used multicolor fluorescence in situ hybridization to show that CRPC CTCs, metastases, and prostate tissue invariably had the same ERG gene status as therapy-naive tumors (n = 31). We then used quantitative reverse transcription–PCR to show that ERG expression was maintained in CRPC. We also observed homogeneity in ERG gene rearrangement status in CTCs (n = 48) in contrast to significant heterogeneity of AR copy number gain and PTEN loss, suggesting that rearrangement of ERG may be an earlier event in prostate carcinogenesis. We finally report a significant association between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of prostate-specific antigen decline (P = 0.007) in CRPC patients treated with abiraterone acetate. These data confirm that CTCs are malignant in origin and indicate that hormone-regulated expression of ERG persists in CRPC. [Cancer Res 2009;69(7):2912–8]

Vascular endothelial growth factor (VEGF) is a key mediator of physiological and pathological angiogenesis. All solid tumors are dependent on pathological angiogenesis, and anti-VEGF therapy has demonstrated clinical benefit in breast, colorectal, non-small-cell lung, and renal carcinomas. Central nervous system metastases are common in many of these tumor types. An increased risk of bleeding has been reported with anti-VEGF therapy, but the risk of intracranial bleeding is unknown with this type of therapy. We reviewed the available data to investigate the risk of intracranial bleeding with anti-VEGF therapy in the presence and absence of CNS metastases. The PubMed and Medline databases and the Proceedings of the American Society of Clinical Oncology (ASCO) annual meetings were searched for articles, abstracts, and presentations of clinical trials. We identified 57 trials examining the safety and efficacy of anti-VEGF therapy in a total of 10,598 patients. Four trials examined the use of anti-VEGF therapy in treating patients with brain metastases. The presence of CNS metastases was a stated exclusion criterion in 76% of trials. The rate of intra cranial bleeding was negligible. We conclude that there is no trial evidence that anti-VEGF therapy confers an increased risk of intracranial bleeding, even in the presence of CNS metastases. Future trials of anti-VEGF therapy should not exclude patients with controlled CNS metastases at enrollment.

Purpose: The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity. Experimental Design: Patients with advanced solid malignancies received CA4P at 45, 54, or 63 mg/m2 on day 1, day 8, and then every 14 days. Bevacizumab 10 mg/kg was given on day 8 and at subsequent cycles four hours after CA4P. Functional imaging with dynamic contrast enhanced-MRI (DCE-MRI) was conducted at baseline, after CA4P alone, and after cycle 1 CA4P + bevacizumab. Results: A total of 63 mg/m2 CA4P + 10 mg/kg bevacizumab q14 is the recommended phase II dose. A total of 15 patients were enrolled. Dose-limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage. Most common toxicities were hypertension, headache, lymphopenia, pruritus, and pyrexia. Asymptomatic electrocardiographic changes were seen in five patients. Nine of 14 patients experienced disease stabilization. A patient with ovarian cancer had a CA125 response lasting for more than a year. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability, which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34+ and CD133+ bone marrow progenitors increased following CA4P as did VEGF and granulocyte colony-stimulating factor levels. Conclusions: CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule. CA4P induced profound vascular changes, which were maintained by the presence of bevacizumab. Clin Cancer Res; 18(12); 3428–39. ©2012 AACR.

Poly(ADP-ribose) polymerase (PARP) is an attractive antitumor target because of its vital role in DNA repair. The homologous recombination (HR) DNA repair pathway is critical for the repair of DNA double-strand breaks and HR deficiency leads to a dependency on error-prone DNA repair mechanisms, with consequent genomic instability and oncogenesis. Tumor-specific HR defects may be exploited through a synthetic lethal approach for the application of anticancer therapeutics, including PARP inhibitors. This theory proposes that targeting genetically defective tumor cells with a specific molecular therapy that inhibits its synthetic lethal gene partner should result in selective tumor cell killing. The demonstration of single-agent antitumor activity and the wide therapeutic index of PARP inhibitors in BRCA1 and BRCA2 mutation carriers with advanced cancers provide strong evidence for the clinical application of this approach. Emerging data also indicate that PARP inhibitors may be effective in sporadic cancers bearing HR defects, supporting a substantially wider role for PARP inhibitors. Drugs targeting this enzyme are now in pivotal clinical trials in patients with sporadic cancers. In this article, the evidence supporting this antitumor synthetic lethal strategy with PARP inhibitors is reviewed, evolving resistance mechanisms and potential molecular predictive biomarker assays are discussed, and the future development of these agents is envisioned.

The development of anticancer drugs remains slow and costly. Use of predictive biomarkers has been postulated to not only accelerate this process but also increase the odds of drug approval ([1][1]). Despite concerns about the validation of the insulin-like growth factor receptor type I (IGF-IR) as

Background: The purpose of this study was to evaluate the association of circulating tumour cell (CTC) counts, before and after commencing treatment, with overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). Experimental design: A 7.5 ml of blood was collected before and after treatment in 119 patients with CRPC. CTCs were enumerated using the CellSearch (R) System. Results: Higher CTC counts associated with baseline characteristics portending aggressive disease. Multivariate analyses indicated that a CTC >= 5 was an independent prognostic factor at all time points evaluated. Patients with baseline CTC >= 5 had shorter OS than those with 30 months, hazard ratio (HR) 3.25, P = 0.012]; patients with CTC > 50 had a poorer OS than those with CTCs 5-50 (median OS 6.3 versus 21.1 months, HR 4.1, P = 5 at baseline to < 5 following treatment had a better OS compared with those who did not. CTC counts showed a similar, but earlier and independent, ability to time to disease progression to predict OS. Conclusion: CTC counts predict OS and provide independent prognostic information to time to disease progression; CTC dynamics following therapy need to be evaluated as an intermediate end point of outcome in randomised phase III trials.

Background: AKT pathway activation is commonly described in ovarian cancer, and implicated in preclinical models of chemoresistance. Ascites occurs in a high proportion of patients at some stage in their illness. Purpose: To study the relationship between activation of the AKT pathway in human ovarian cancer ascites specimens (measured by the ratio of phosphorylated (P) to total (T) AKT pathway proteins) to patient survival and response to chemotherapy. In addition we studied the correlation of P/T AKT ratio to carboplatin sensitivity in a human ovarian cancer cell line panel. Method. 99 samples of ascites from 75 patients with ovarian cancer and a known treatment history were purified using anti-EpCam antibody coated magnetic beads (Dynal Biotech), stored at −80 degrees C, and then analysed with Mesoscale Discovery (MSD) ELISA for P/T AKT, GSK3β and p70S6K, and Pathscan ELISA for P/T 4EBP1 . Differences in survival in patient subgroups were analysed by logrank tests. Five cell lines (A2780, CH1, IGROV1, OVCAR3, SKOV3) were analysed in triplicate by sulphurhodamine B colorimetric assay to establish half maximal inhibitory concentration (IC50) for carboplatin and PI3K-AKT-mTOR pathway inhibitors (rapamycin, LY 294002, PI103, and Merck AKT inhibitor VIII), and the results correlated with baseline AKT pathway protein activation ratios. Results: Samples from patients who responded to chemotherapy (n=32) subsequent to sample collection had a lower median P/T S6K ratio (0.43) than those (n=28) who progressed (0.71, p=0.026, Mann-Whitney test; 39 samples were from patients who received no subsequent chemotherapy). Analysing the first sample for each patient, (n=75), those with a P/T AKT ratio above median (0.140) had a statistically significantly longer survival than those patients below median (28.0 months (m) vs 49.7 m, HR 1.74 (95% CI 1.01-3.01), p=0.048). A similar trend for P/T S6K ratio was also found, however this was not statistically significant (22.0 m vs 47.5 m, HR 1.56 (95%CI 0.90-2.71), p=0.112). In the ovarian cell line panel studied, a high P/T AKT ratio was found in the cells most resistant to carboplatin, whereas there was no relationship between AKT pathway activation and resistance to the AKT pathway inhibitors. Potential reasons for activation of the AKT pathway include amplification and mutation of PIK3CA and AKT2. Fluorescence in-situ hybridisation and sequencing of somatic DNA from these samples are ongoing. Conclusion: Patients who responded to subsequent chemotherapy had a significantly lower P/T S6K ratio than those who progressed. A P/T AKT ratio greater than 0.144 in malignant ascites predicts a statistically significant poorer prognosis. In vitro cell line models suggest a trend of P/T AKT ratio to correlate with carboplatin resistance. P/T AKT ratio should be studied prospectively as a prognostic and predictive biomarker in ovarian cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 788.

Background: OSI-906 is a potent small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF-1R), a receptor tyrosine kinase that is overexpressed in several human cancer types and implicated in resistance to chemotherapy. Disruption of the growth hormone-IGF1 signaling axis can affect levels of biomarkers such as IGF1, growth hormone (GH) and insulin and can affect glucose homeostasis, making these potentially useful markers for demonstrating the activity of IGF-1R inhibitors in solid tissues. Methods: Two phase I dose escalation trials were initiated in cancer patients with advanced solid tumors who received OSI-906 on either continuous or intermittent dosing schedules. Pharmacodynamic (PD) and pharmacokinetic (PK) assessments were included as secondary objectives of these studies. Circulating biomarkers, including total IGF1, IGFBP3 and non-fasting GH and insulin levels, were measured at various times during the dosing cycle (21 days for continuous dosing; 14 days for intermittent dosing) and changes were correlated with plasma concentrations of OSI-906. Results: To date, patients have been treated with up to 450 mg QD and 200 mg BID on the continuous dosing schedule and up to 750 mg QD on the intermittent dosing schedule. Maximum tolerated dose (MTD) was determined to be 400 mg QD and 150 mg BID for continuous dosing and 600 mg QD for intermittent dosing. Preliminary analysis of the PK data suggests that the exposure of OSI-906 increased with dose. Median plasma concentrations of OSI-906 at MTD exceeded the predicted concentration required for efficacy based on the preclinical models (1 µM). Total IGF1 concentrations in plasma were increased relative to predose levels at doses ≥ 450 mg QD on the intermittent dosing schedule and ≥ 150 mg QD or 40 mg BID on the continuous dosing schedule. Elevations in non-fasting plasma insulin levels were also observed in patients with plasma concentrations of OSI-906 exceeding 5000 ng/mL. PK/PD relationships were observed for IGF1 and insulin. OSI-906 did not affect plasma IGFBP3 levels in most patients. Analysis of additional biomarkers, including GH, is ongoing. Conclusions: At or below MTD, plasma concentrations of OSI-906 could be achieved that exceed concentrations required for anti-tumor efficacy based on the preclinical models. The pharmacodynamic data indicate that pharmacologically-relevant concentrations of OSI-906 were achieved in tissues involved in regulating the GH-IGF1 signaling axis. Together, these PK and PD data indicate that the current recommended dosing regimens may provide sufficient exposure for activity against solid tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A46.