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  • American Association for Cancer Research (AACR)  (22)
  • 1
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    Integrative Molecular Characterization of Malignant Pleural Mesothelioma
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Discovery Vol. 8, No. 12 ( 2018-12-01), p. 1548-1565
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 12 ( 2018-12-01), p. 1548-1565
    Abstract: Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. Significance: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM. See related commentary by Aggarwal and Albelda, p. 1508. This article is highlighted in the In This Issue feature, p. 1494
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-18-0804
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2607892-2
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  • 2
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    Abstract C106: Pediatric Preclinical Testing Program (PPTP) Stage 1 evaluation of the PI3K inhibitor XL147 (SAR245408).
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. C106-C106
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. C106-C106
    Abstract: Introduction: XL147 is a potent, orally bioavailable inhibitor of the class I PI3K family of lipid kinases with IC50 values in the nanomolar range in biochemical assays. XL147 inhibits phosphorylation of downstream effectors of PI3K in preclinical models as well as in surrogate tissues and tumors in adults with cancer. XL147 is under clinical evaluation for adults with cancer in combination with certain cytotoxic agents as well as with other cell signaling pathway inhibitors (e.g., the MEK inhibitor MSC1936369B). The activity of XL147 was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical testing Program (PPTP). Methods: XL147 was tested against the PPTP's in vitro cell line panel at concentrations ranging from 10.0 nM to 100 μM using the PPTP's standard 96 hour exposure period. For in vivo testing, an XL147 dose of 100 mg/kg administered orally daily for 14 days with a total planned observation period of 6 weeks. Results: XL147 demonstrated cytotoxic activity, with Ymin values approaching 0% for all of the cell lines at the highest concentration tested (100 μM). The median relative IC50 value for the PPTP cell lines was 10.9 μM, with a range from 2.7 μM (CHLA-10) to 24.5 μM (TC-71). There were no significant differences by histotype in median relative IC50 values, though there was a trend for lower values for the rhabdomyosarcoma panel (median IC50 5.6 μM) and higher values for the neuroblastoma panel (median IC50 19.5 μM). XL147 was tested against 31 solid tumor xenografts and 7 acute lymphoblastic leukemia (ALL) xenografts. A dose of 100 mg/kg administered orally daily for 14 days for a total planned observation period of 6 weeks was utilized. XL147 was generally well tolerated, with a & lt;1% toxicity rate in the treated groups, similar to that observed for control animals. XL147 induced significant differences in EFS distribution compared to control in 26 of 30 (87%) of the evaluable solid tumor xenografts and in 2 of 7 (29%) of the evaluable ALL xenografts. XL147 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C & gt; 2) in 3 of 29 (10%) evaluable solid tumor xenografts (2 of 6 rhabdomyosarcoma and 1 of 5 neuroblastoma), and intermediate or high EFS T/C activity was observed for 2 of 7 (29%) evaluable ALL xenografts. Basal levels of activation of PI3K signaling, as assessed by phospho-AKT, levels did not correlate with in vivo response to XL147. Expression of PI3K isoforms at the RNA level was evaluated using Affymetrix U133 Plus 2.0 arrays, with the most striking observation being the pattern of expression of PIK3CD, which was virtually restricted to the ALL and lymphoma cell lines and xenografts, as would be expected from the hematopoietic cell specificity of this isoform in normal tissues. Conclusions: Under the conditions evaluated in this study, XL147 achieved modest single-agent activity against the PPTP preclinical models. Available data suggests that genomic activation of PI3K signaling (e.g., through PIK3CA mutation or PTEN deletion) is less common in the pediatric solid tumors setting compared to the adult cancer setting, which may explain the limited single agent activity. Preclinical evaluations of XL147 in combination with particular standard agents and with other pathway signaling inhibitors are planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C106.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-C106
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 3
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    Abstract C57: Pediatric Preclinical Testing Program (PPTP) Stage 1 evaluation of AZD8055 an inhibitor of mTOR Kinase
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. C57-C57
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. C57-C57
    Abstract: Background: The serine/threonine kinase mTOR in the mTORC1 complex plays an important role in regulating cap-dependent translation and in the mTORC2 complex is required to fully activate Akt signaling. AZD8055 is a small molecule being evaluated in phase 1 clinical trials that selectively inhibits mTOR kinase in both complexes. The activity of AZD8055 was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical testing Program (PPTP). Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood ALL. AZD8055 was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 µM to determine the IC50 (concentration at which T/C% = 50%) and the minimum T/C%, and it was tested against the PPTP in vivo panel at a dose of 20 mg/kg daily by oral gavage for 4 consecutive weeks. Three measures of antitumor activity were used: 1) response criteria modeled after the clinical setting; 2) treated to control (T/C) tumor volume at day 21; and 3) a time to event (4-fold increase in tumor volume) measure based on the median EFS of treated and control lines (intermediate activity required EFS T/C & gt; 2, and high activity additionally required a net reduction in median tumor volume at the end of the experiment). Results: AZD8055 potently inhibited growth of the PPTP cell lines with a median IC50 value for the in vitro panel of 31.7 nM (range 2.6 nM to & gt; 10 µM) and a minimum T/C% value of 6.2% (range 0.1% to 62.3%). AZD8055 was well tolerated in vivo (4.3% lethality), with only 3 of 45 tested xenograft models considered non-evaluable because of toxicity. AZD8055 induced significant differences in EFS distribution compared to control in 23 of 36 (64%) of the solid tumor xenografts and in 1 of 6 (17%) of the ALL xenografts. Criteria for intermediate activity for the time to event activity measure (i.e., EFS T/C & gt; 2) were met in 5 of 32 (16%) solid tumor xenografts evaluable for this measure and were observed in the rhabdomyosarcoma panel (3 of 6) and Ewing sarcoma panel (2 of 5). Tumor regression was not observed at the 20 mg/kg daily dose, with the best response being stable disease, which was observed in 2 of 36 (5.6%) evaluable solid tumor xenografts. PD2 (progressive disease with growth delay) was observed in 20 of 36 (55.6%) evaluable solid tumor xenografts, including 4 of 5 Ewing sarcoma and 4 of 6 rhabdomyosarcoma xenografts. Conclusions: The activity observed for AZD8055 against the PPTP preclinical models is modest, although a subset of PPTP xenografts in the rhabdomyosarcoma and Ewing sarcoma panels showed greater tumor growth inhibition compared to other solid tumor xenografts. Future studies will focus on defining how the pharmacokinetics and the pharmacodynamic effects of AZD8055 relate to tumor sensitivity and on evaluating combinations of AZD8055 with standard cytotoxic agents. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C57.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-C57
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 4
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    Phase I Trial of a New Schedule of Romidepsin in Patients with Advanced Cancers
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 16 ( 2013-08-15), p. 4499-4507
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 16 ( 2013-08-15), p. 4499-4507
    Abstract: Purpose: Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers. Experimental Design: Open-label, single-arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes. Results: Twenty-eight patients with solid tumors, including 11 patients with thyroid cancer were enrolled. Six dose levels were explored, and 7 mg/m2 on days 1, 3, and 5 was identified as tolerable. No Response Evaluation Criteria In Solid Tumors–defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range, 21–112) including 6 with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases. Conclusions: A romidepsin dose of 7 mg/m2 administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors. Clin Cancer Res; 19(16); 4499–507. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-0095
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 5
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    Abstract 4127: A prospective study of breast cancer prognosis in Kaiser Permanente Northern California: Cohort description and initial findings from the Pathways Study
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4127-4127
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4127-4127
    Abstract: Background: With over 2.8 million breast cancer survivors in the U.S. today, there is increasing interest and need to identify factors associated with recurrence and survival. The Pathways Study was designed to examine the effects of lifestyle (e.g., diet, physical activity, complementary and alternative medicine [CAM]), psychosocial (e.g., quality of life), molecular and genetic, medical care, and contextual (e.g., social and built environment characteristics) factors on breast cancer prognosis. Methods: Women newly-diagnosed with invasive breast cancer were identified daily from Kaiser Permanente Northern California (KPNC) electronic pathology records from January 2006 to April 2013; KPNC is a large, integrated health care organization. Eligibility included age at diagnosis of at least 21 y, no previous history of invasive cancer, and English, Spanish or Chinese-speaking. Women were enrolled during an in-person baseline interview that took place on average two months post-diagnosis, with collection of blood and saliva specimens. Active follow-up to update lifestyle and other factors and ascertain outcomes occurs periodically. Outcomes are also identified using KPNC electronic databases and confirmed via medical record review. Results: The final study cohort consists of 4,505 women, with blood and saliva collected from 90% and 95% of participants, respectively. The cohort has substantial racial/ethnic diversity: 64.2% White, 12.4% Hispanic, 12.8% Asian, 7.9% African American, 2.7% other. The mean age at diagnosis was 59.6 y (range: 23.6-94.8 y). Educational attainment is high, with 84.1% of the cohort having at least some college education. Most women were diagnosed with AJCC Stage I (54.0%) or II (34.6%) cancers, and receptor status was positive for estrogen in 83% of women, progesterone in 63.4%, and Her2 in 12.3%. As of December 1, 2013, 307 recurrences and 327 deaths have been confirmed, with 490 experiencing either. Initial age-adjusted results with proportional hazards regression demonstrate poorer disease-free survival (DFS) among African Americans (hazard ratio [HR]=1.84, 95% confidence interval [CI] ,1.39-2.45) and better DFS among Asians (HR=0.70, 95% CI, 0.49, 1.00) compared to Whites. Greater stage at diagnosis, increasing age, and negative ER status are also associated with poorer DFS. Discussion: The Pathways Study is a rich, unique resource collecting data on multiple factors that may influence breast cancer prognosis, including lifestyle, molecular, medical, and contextual factors. To date, 14 papers have been published on topics ranging from CAM use, quality of life, and physical activity during treatment, to tumor DNA methylation profiles and correlates of breast cancer molecular subtypes. With continued follow-up, it promises to provide findings on factors influencing prognosis to help guide breast cancer care. Citation Format: Lawrence H. Kushi, Marilyn L. Kwan, Isaac J. Ergas, Cecile A. Laurent, Julie R. Munneke, Janise M. Roh, Heather Greenlee, Chi-Chen Hong, Theresa H. Keegan, Dawn L. Hershman, Susan E. Kutner, Marion M. Lee, Jeanne Mandelblatt, Alfred I. Neugut, Peggy Reynolds, Salma Shariff-Marco, Li Tang, Song Yao, Janice Barlow, Scarlett Lin Gomez, John K. Wiencke, Christine B. Ambrosone. A prospective study of breast cancer prognosis in Kaiser Permanente Northern California: Cohort description and initial findings from the Pathways Study. [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 4127. doi:10.1158/1538-7445.AM2014-4127
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-4127
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract 1615: Initial testing (stage 1) of the Curaxin, CBL0137, by the Pediatric Preclinical Testing Program (PPTP)
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1615-1615
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1615-1615
    Abstract: The Curaxin, CBL0137, is a member of a new class of small molecules that simultaneously activate p53 and inhibit cancer-associated stress response pathways such as NFκB and Heat Shock Factor 1. CBL0137 sequesters the FACT (FAcilitates Chromatin Transcription) complex on chromatin, inhibiting its function. CBL0137 has shown antitumor activity against a broad range of tumor models. Because of its novel mechanism of action CBL0137 was evaluated for its antitumor activity against the PPTP in vitro and in vivo models. Methods: CBL0137 was tested against the PPTP's in vitro cell line panel (n = 23) at concentrations ranging from 1.0 nM to 10.0 μM using the PPTP's standard 96 hour exposure period. CBL0137 was tested against the PPTP solid tumor xenografts using a dose of 50 mg/kg administered by the intravenous route weekly for 4 weeks. Standard PPTP time to event and objective response metrics were used to assess CBL0137 in vivo activity. Results: The median relative IC50 (rIC50) value for the PPTP cell lines was 0.28 μM, with a range from 0.13 μM to 0.80 μM. There were no significant differences in rIC50 values by histotype. The median rIC50 for the neuroblastoma cell lines exceeded that of the non-neuroblastoma cell lines (0.51 μM vs 0.26 μM, respectively, p = 0.16), while the median rIC50 for the ALL cell lines was less than that of the non-ALL cell lines (0.20 μM vs 0.31 μM, respectively, p = 0.06). All PPTP cell lines showed a pronounced cytotoxic effect, with T/C Ymin% values approaching 0% and with Relative I/O% values approaching -100% for all cell lines at the higher concentrations tested. CBL0137 was generally well tolerated in vivo with a 3.1% toxicity rate in the treated groups compared to a 0.8% rate for control animals. CBL0137 induced significant differences in EFS distribution compared to control in 9 of 30 (30%) of the solid tumor xenografts evaluable for this measure and in 8 of 8 (100%) evaluable ALL xenografts. Significance differences in EFS distributon were observed in 4 of 6 osteosarcoma lines, 2 of 2 rhabdoid tumor lines, and 2 of 6 rhabdomyosarcoma lines. No objective responses were observed among the 30 solid tumor xenografts. For the ALL panel, 1 xenograft achieved CR and 4 achieved PR. In summary, CBL0137 showed potent cytotoxic activity in vitro without clear histotype selectivity. In vivo the most consistent activity for CBL0137 was observed against the ALL xenografts, with most solid tumor xenograft lines showing limited response to single agent CBL0137. In considering clinical translation of these testing results, it will be important to relate the drug levels in SCID (soid tumor models) or NOD/SCID (ALL models) mice at 50 mg/kg to those tolerated in humans at the CBL0137 recommended phase 2 dose. Citation Format: Malcolm A. Smith, Min Kang, Patrick C. Reynolds, Richard B. Lock, Hernan Carol, Richard Gorlick, Anders E. Kolb, John M. Maris, Stephen T. Keir, Catherine A. Billups, Raushan Kurmasheva, Peter J. Houghton. Initial testing (stage 1) of the Curaxin, CBL0137, by the Pediatric Preclinical Testing Program (PPTP). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1615. doi:10.1158/1538-7445.AM2015-1615
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-1615
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 7
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    Abstract 5356: Pediatric preclinical testing program (PPTP) evaluation of the DNA methylating agent temozolomide
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5356-5356
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5356-5356
    Abstract: Background: Temozolomide is DNA methylating agent that has been approved in the United States for treatment of astrocytoma. This drug in many ways resembles more established compounds, such as dacarbazine and procarbazine, in that it gives rise to a methyl diazonium ion that attacks nucleophilic sites including the O6-guanine position in DNA. Temozolomide, however, differs from these drugs, which have to be activated by enzymatic oxidation, in that it degrades spontaneously via base-catalyzed hydrolysis to the final active methylating species. Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood acute lymphoblastic leukemia (ALL). Temozolomide (provided by the NCI Drug Repository) was tested in vitro at concentrations from 100 nM to 1 mM. Temozolomide was administered PO using a daily × 5 schedule repeated at 21 days at a dose of 100 mg/kg, or 66 mg/kg. Three measures of antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a treated to control (T/C) tumor volume measure; and 3) a time to event (4-fold increase in tumor volume) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. Biomarkers of temozolomide sensitivity, MGMT, MLH1, MSH2 and p53 genotype were determined. Results: The median temozolomide IC50 value for the PPTP cell lines was 380 μM (range 2 to & gt; 1000 μM), with the neuroblastoma cell line NB-1643 having the lowest IC50 value. There were no significant differences in IC50 values between the rhabdomyosarcoma, neuroblastoma, Ewing sarcoma, and ALL cell lines. In vivo temozolomide induced significant toxicity at 100 mg/kg resulting in exclusion of 10/42 lines from analysis. For the 32 lines evaluable there were 13 maintained complete responses (MCR) and 2 CR in the solid tumor panels and 3 MCR and 2 CR in the ALL panel. Retesting the excluded lines at 66 mg/kg resulted in excessive toxicity leading to exclusion of 2/9 lines. At this dose there were 2 MCR and progressive disease in the remaining 5 lines. Overall 17/30 tumor models demonstrated objective responses (≥PR). Of these 7 are MGMT-negative, 3 are MLH1-negative, and 11 have wild type p53. All 7/7 MGMT-negative tumors responded, irrespective of p53 genotype (5/7 wild type). Conclusions: In vitro temozolomide induced cytotoxicity with no apparent cell type specificity. In vivo temozolomide demonstrated high activity, but with a steep dose response curve, consistent with other DNA damaging agents. Responses poorly correlated with MGMT, MLH1, MSH2 levels, or p53 genotype. However, all MGMT-negative tumors were responsive, irrespective of MLH1 or p53 status. The results suggest that temozolomide may have potential for treatment of a range of pediatric malignancies. (Supported by NO1-CM91003-03) 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 5356. doi:10.1158/1538-7445.AM2011-5356
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-5356
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
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  • 8
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    Abstract 5358: Pediatric preclinical testing program (PPTP) evaluation of the non-camptothecin topoisomerase 1 targeted agent Genz644282
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5358-5358
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5358-5358
    Abstract: Background: Genz644282, a non camptothecin topoisomerase I poison, was developed from a lead compound 8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5-H-dibenzo[c,h] [1,6] naphthyridin-6-one (ARC111, topovale). In non-clinical testing ARC111 had equivalent or superior activity to irinotecan, and induced regression in a topotecan insensitive tumor xenograft. ARC111 also differentiated itself from other camptothecin derivatives in that it was not a substrate for the ABCG2 drug transporter. Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood acute lymphoblastic leukemia (ALL). Genz664282 (provided by Genzyme Corporation) was tested in vitro at concentrations from 0.1 nM to 1 μM with 96 hr exposure to drug. Genz664282 was administered IP, three times weekly for 2 weeks at a dose of 1 – 4 mg/kg for either 1 or two cycles. Three measures of antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a treated to control (T/C) tumor volume measure; and 3) a time to event (4-fold increase in tumor volume) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. Results: In vitro Genz644282 exerted potent cytotoxic activity with a median IC50 of 1.19 nM (range 0.186 – 23.3 nM). There was no cell type selectivity. In vivo at 4 mg/kg (MTD) for two cycles, Genz644282 induced maintained complete responses (MCR) in 8/8 models including tumor lines poorly responsive to topotecan. Dose response evaluation (1 cycle of treatment) against 3 tumor lines least sensitive to topotecan showed Genz644282 induced 2MCR and 1CR at 4 mg/kg, and 2CR and 1 MCR at 2 mg/kg, but no regressions were observed at 1 mg/kg, suggesting a steep dose response relationship. Further testing at 2 mg/kg (1 cycle) induced 4MCR, 1CR and 2PR in 17 tumor lines (41%), mainly in sarcoma models (6/7), particularly osteosarcoma (4/6). Conclusions: At the 2 mg/kg dose level administered for one cycle of treatment, Genz644282 demonstrated a high level of activity inducing regressions in 7 of 17 models evaluated, with particularly high activity in osteosarcoma models. The models included tumors intrinsically insensitive to topotecan. As with other topoisomerase I poisons, how accurately this data will translate to clinical activity will depend upon the drug exposures that can be achieved in children treated with this agent. (Supported by NO1-CM91003-03) 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 5358. doi:10.1158/1538-7445.AM2011-5358
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-5358
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 9
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    Abstract 1104: Insulin-like growth factor-1 is elevated in viscerally obese oesophageal adenocarcinoma patients and expression of its receptor correlates with tumor invasiveness
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1104-1104
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1104-1104
    Abstract: The insulin-like growth factor (IGF) pathway and visceral obesity have been independently linked with esophageal cancer development. This study aimed to delineate the differential and interlinked role of visceral obesity and the IGF-1 system in esophageal adenocarcinoma and squamous cell carcinoma (SCC) progression. IGF-1 receptor (IGF-1R) mRNA and protein were examined in esophageal SCC (KYSE410, OE21) and adenocarcinoma (OE19, OE33) cell lines by Western Blotting. Tumor cell proliferation in response to IGF-1 was assessed by BrdU incorporation assay. Circulating levels of IGF-1 were measured in 99 serum samples by ELISA and IGF-1R expression was assessed in 50 resected tumor specimens by immunohistochemistry. Results were related to tumor type, gender and visceral adiposity. Higher IGF-1R mRNA and protein expression were observed in SCC cells, however only adenocarcinoma cell lines showed significantly increased cell proliferation in response to IGF-1 (p & lt;0.01). Significantly higher circulating levels of IGF-1 were detected in patients who had adenocarcinoma (p & lt;0.05) and who were viscerally obese (p & lt;0.05). In resected esophageal adenocarcinoma, IGF-1R expression significantly increased as the tissue progressed along the malignant sequence, with the highest expression observed at the invasive leading edge of the tumor. Uniform IGF-1R expression was observed in SCC tumors. This novel study is the first of its kind to examine both the differential role of the IGF system in esophageal adenocarcinoma and SCC, and also its association with visceral obesity. These data indicate that in esophageal adenocarcinoma, the IGF-1 axis plays a key role in malignant progression and represents a plausible mechanism by which visceral obesity increases esophageal adenocarcinoma risk. 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 1104. doi:10.1158/1538-7445.AM2011-1104
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-1104
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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    Abstract LB-B13: Pediatric Preclinical Testing Consortium evaluation of the CHK1 inhibitor prexasertib
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. LB-B13-LB-B13
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. LB-B13-LB-B13
    Abstract: Introduction: Prexasertib is a CHK1 inhibitor that has entered clinical evaluation in adults and children with cancer. CHK1 plays a central role in pausing cell cycle progression in response to DNA damage, and an RNAi screen identified CHK1 as a therapeutic target for neuroblastoma (Cole KA, PNAS 2011; 108: 3336-41). Methods: Prexasertib was tested in vitro against a 23 cell line panel at concentrations from 0.1 nM to 1 µM. In vivo treatment groups included: prexasertib at 7.5 and 10 mg/kg given BID on days 1-3 x 3 weeks (Regimen [Reg] F & B, respectively); prexasertib at 4 mg/kg given BID days 1, 3, 5 (Reg C); irinotecan (IR) at 2.5 mg/kg days 1-5 (Reg D); and the combination of the agents (Reg E) with prexasertib as per Reg C and IR as per Reg D. For solid tumor testing, events are defined as 4X increase in tumor volume from day 0 and for CNS tumor testing as animals becoming moribund or developing severe neurologic deficit. The Kaplan-Meier method was used to compare EFS between treated and control groups. The objective response categories are progressive disease (PD, which is subdivided into progressive disease without and with growth delay, PD1 and PD2 respectively), stable disease (SD), partial response (PR), complete response (CR) and maintained complete response (MCR) (Houghton PJ, et al. Pediatr Blood Cancer 2007;49:928-40). Prexasertib was provided for testing by Lilly. Results: The prexasertib median IC50 for the pediatric cell lines was 3.2 nM, with a range from 0.9 nM to 22 nM and with no evidence for histotype specificity. Prexasertib as a single agent at 7.5 mg/kg consistently slowed tumor growth but failed to induce regressions in the 9 xenograft lines tested. Prexasertib at 10 mg/kg induced PR or CR in 6 of 6 neuroblastoma, 1 of 2 rhabdomyosarcoma, 0 of 1 Ewing sarcoma, and 0 of 2 osteosarcoma xenografts tested, and it induced a MCR in a rhabdoid tumor xenograft. Prexasertib single agent activity was comparable to that observed for single agent IR. The combination of IR and prexasertib (4 mg/kg) was significantly better than prexasertib (10 mg/kg) at prolonging EFS for only 1 of 6 NB, and the combination was significantly better than single agent IR for only 1 of 6 NB. For the remaining 7 xenograft lines, the combination was significantly superior to single agent IR for 3 lines (2 OS and 1 rhabdoid tumor), but the combination was significantly inferior to prexasertib (10 mg/kg) for the rhabdoid tumor line. Prexasertib had no effect as a single agent or in combination with XRT for two orthotopic medulloblastoma xenografts. Conclusions: Prexasertib at 10 mg/kg shows consistent tumor regressing activity as a single agent for neuroblastoma xenografts, confirming recently published data (Lowery, et al. CCR 23: 4354-63, 2017), and it shows tumor regressing activity for other histotypes. The limited activity of prexasertib at 7.5 mg/kg suggests a dose-response effect and that clinical trial design should seek the highest tolerated dose in children. For most xenografts, the combination of IR with prexasertib (at a reduced dose as required for tolerability) was no better than either single agent prexasertib at an optimized dose/schedule or single agent IR. An important area for future research is identifying agents that can be effectively combined with prexasertib for neuroblastoma and other childhood cancers. (Supported by NCI Grants/Contracts: CA199222, CA199221; CA199297; CA199288; CA199287; NO1-CM-42216) Citation Format: Kristina A. Cole, Peter J. Houghton, Raushan T. Kurmasheva, Richard Gorlick, E. Anders Kolb, Min Kang, C. Patrick Reynolds, Xiao-Nan Li, Holly Lindsay, Stephen W. Erickson, Yuelong Guo, Beverly A. Teicher, Malcolm A. Smith, John M. Maris. Pediatric Preclinical Testing Consortium evaluation of the CHK1 inhibitor prexasertib [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B13.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-LB-B13
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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