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  • American Association for Cancer Research (AACR)  (34)
  • 1
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    Abstract PR03: Genomic approaches for risk assessment in acute myeloid leukemia
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 22_Supplement_2 ( 2015-11-15), p. PR03-PR03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 22_Supplement_2 ( 2015-11-15), p. PR03-PR03
    Abstract: Acute myeloid leukemia is heterogeneous with respect to clinical outcome and molecular pathogenesis. Approximately 20% of AML cases are refractory to induction chemotherapy, and about 50% of patients ultimately relapse within a time interval that ranges from months to years. At the molecular level, diverse chromosomal abnormalities and genetic mutations have been observed across patients1. Although several clinical factors (age, white blood cell count), cytogenetic aberrations (t[15;17] translocation, loss of chromosome 5) 2-4, and genetic mutations (DNMT3A, FLT3) have been associated with differences in survival 5,6, these factors are of limited prognostic utility. Moreover, few studies have integrated sequence data with clinical and cytogentic factors to build predictive models of patient outcome. Here, we sought to identify genomic predictors of refractory disease or early relapse. We used whole genome and exome sequencing to analyze the genomes of 71 adult de novo AML patients treated with anthracycline and cytarabine-based induction chemotherapy. Of these, 34 had refractory disease or relapsed within 6 months, 12 relapsed in 6-12 months, and 25 had a long first remission ( & gt;12 months). We also developed an enhanced exome sequencing (EES) approach to identify and follow leukemia-associated variants over time. In 12 additional patients that achieved morphologic remission after induction chemotherapy, we used EES to identify and track variants at time of diagnosis, time of morphologic remission (roughly 30 days later), and a final time point corresponding to eventual relapse (n=8) or extended remission (n=4). No novel coding or non-coding variants present at the time of diagnosis were found to be predictive of refractory disease or early relapse. Using EES, however, we were able to detect leukemia-associated variants in the initial remission bone marrow in all eight patients who eventually relapsed. One persistent leukemia-associated variant was also detected in one patient still in remission, but all other variants in that patient were eliminated. We also detected 64 somatic variants that became enriched following chemotherapy, but were not detected in the original leukemic cells. These may represent relapse-specific variants or oligoclonal hematopoiesis after bone marrow recovery. Overall, our data suggest that the persistence of leukemia-associated variants after bone marrow recovery from cytotoxic therapy is strongly correlated with relapse, and may be used to complement more traditional, morphologic measures of leukemic cell clearance. 1. Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. The New England Journal of Medicine 2013;368:2059-74. 2. Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325-36. 3. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010;116:354-65. 4. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. The New England Journal of Medicine 2008;358:1909-18. 5. Kihara R, Nagata Y, Kiyoi H, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia 2014;28:1586-95. 6. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. The New England Journal of Medicine 2010;363:2424-33. This abstract is also presented as a poster at the Translation of the Cancer Genome conference. Citation Format: Jeffery M. Klco, Christopher A. Miller, Malachi Griffith, Allegra Petti, David H. Spencer, Shamika Ketkar-Kulkarni, Lukas D. Wartman, Matthew Christopher, Tamara L. Lamprecht, Jacqueline E. Payton, Jack Baty, Sharon E. Heath, Obi L. Griffith, Dong Shen, Jasreet Hundal, Gue Su Chang, Robert S. Fulton, Michelle O'laughlin, Catrina Fronick, Vincent Magrini, Ryan Demeter, David E. Larson, Shashikant Kulkarni, Bradley A. Ozenberger, John S. Welch, Matthew J. Walker, Timothy A. Graubert, Peter Westervelt, Jerald P. Radich, Daniel C. Link, Elaine R. Mardis, John F. DiPersio, Richard K. Wilson. Genomic approaches for risk assessment in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.COMPSYSBIO-PR03
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 2
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    Abstract PR11: Genomic approaches for risk assessment in acute myeloid leukemia
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 22_Supplement_1 ( 2015-11-15), p. PR11-PR11
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 22_Supplement_1 ( 2015-11-15), p. PR11-PR11
    Abstract: Acute myeloid leukemia is heterogeneous with respect to clinical outcome and molecular pathogenesis. Approximately 20% of AML cases are refractory to induction chemotherapy, and about 50% of patients ultimately relapse within a time interval that ranges from months to years. At the molecular level, diverse chromosomal abnormalities and genetic mutations have been observed across patients1. Although several clinical factors (age, white blood cell count), cytogenetic aberrations (t[15;17] translocation, loss of chromosome 5) 2-4, and genetic mutations (DNMT3A, FLT3) have been associated with differences in survival 5,6, these factors are of limited prognostic utility. Moreover, few studies have integrated sequence data with clinical and cytogentic factors to build predictive models of patient outcome. Here, we sought to identify genomic predictors of refractory disease or early relapse. We used whole genome and exome sequencing to analyze the genomes of 71 adult de novo AML patients treated with anthracycline and cytarabine-based induction chemotherapy. Of these, 34 had refractory disease or relapsed within 6 months, 12 relapsed in 6-12 months, and 25 had a long first remission ( & gt;12 months). We also developed an enhanced exome sequencing (EES) approach to identify and follow leukemia-associated variants over time. In 12 additional patients that achieved morphologic remission after induction chemotherapy, we used EES to identify and track variants at time of diagnosis, time of morphologic remission (roughly 30 days later), and a final time point corresponding to eventual relapse (n=8) or extended remission (n=4). No novel coding or non-coding variants present at the time of diagnosis were found to be predictive of refractory disease or early relapse. Using EES, however, we were able to detect leukemia-associated variants in the initial remission bone marrow in all eight patients who eventually relapsed. One persistent leukemia-associated variant was also detected in one patient still in remission, but all other variants in that patient were eliminated. We also detected 64 somatic variants that became enriched following chemotherapy, but were not detected in the original leukemic cells. These may represent relapse-specific variants or oligoclonal hematopoiesis after bone marrow recovery. Overall, our data suggest that the persistence of leukemia-associated variants after bone marrow recovery from cytotoxic therapy is strongly correlated with relapse, and may be used to complement more traditional, morphologic measures of leukemic cell clearance. 1. Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. The New England Journal of Medicine 2013;368:2059-74. 2. Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325-36. 3. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010;116:354-65. 4. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. The New England Journal of Medicine 2008;358:1909-18. 5. Kihara R, Nagata Y, Kiyoi H, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia 2014;28:1586-95. 6. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. The New England Journal of Medicine 2010;363:2424-33. Citation Format: Jeffery M. Klco, Christopher A. Miller, Malachi Griffith, Allegra Petti, David H. Spencer, Shamika Ketkar-Kulkarni, Lukas D. Wartman, Matthew Christopher, Tamara L. Lamprecht, Jacqueline E. Payton, Jack Baty, Sharon E. Heath, Obi L. Griffith, Dong Shen, Jasreet Hundal, Gue Su Chang, Robert S. Fulton, Michelle O'laughlin, Catrina Fronick, Vincent Magrini, Ryan Demeter, David E. Larson, Shashikant Kulkarni, Bradley A. Ozenberger, John S. Welch, Matthew J. Walker, Timothy A. Graubert, Peter Westervelt, Jerald P. Radich, Daniel C. Link, Elaine R. Mardis, John F. DiPersio, Richard K. Wilson. Genomic approaches for risk assessment in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR11.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TRANSCAGEN-PR11
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    Abstract A38: Development and implementation of immunohistochemistry (IHC)-based pharmacodynamic (PD) biomarkers demonstrate NAE pathway inhibition in MLN4924 solid tumor clinical trials.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. A38-A38
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. A38-A38
    Abstract: MLN4924 is an investigational small molecule NEDD8 activating enzyme (NAE) inhibitor with antitumor activity in preclinical models of several tumor types that is currently in Phase I clinical development in both hematological and solid tumors. NAE is an essential controller of the NEDD8 conjugation pathway that is required for cullin-RING ligase (CRL) activity. MLN4924 forms a covalent adduct with NAE, inhibiting enzyme activity and thus preventing ubiquitination and proteasomal degradation of CRL substrate proteins. CRL substrates have important roles in cell-cycle progression, DNA replication (CDT1), oxidative stress response (NRF-2), and survival signaling; interfering with their degradation ultimately leads to apoptosis. MLN4924 is the first NAE inhibitor to enter clinical development and evidence of target inhibition and/or downstream pathway modulation were key objectives of the Phase I studies. Here we describe the development, validation and clinical implementation of IHC PD assays for MLN4924 that quantify levels of CRL substrates CDT1 and NRF-2 and demonstrate MLN-4924 NEDD8 adduct formation in both skin and solid tumors. Pre-clinical solid tumor xenograft models were treated with increasing doses of MLN4924. Tumors were collected at multiple post-dose time points (30 minutes to 48 hours) to develop clinical assays and establish the biopsy schedule. Levels of stabilized substrates CDT1 and NRF-2, and presence of MLN4924-NEDD8 adduct were measured by quantitative and semi-quantitative IHC, respectively. Slides were scanned as whole slide images using an Aperio XTscan scope and analyzed for a percent positive pixel count using Metamorph imaging software. Western blotting of xenograft material showed decreased cullin neddylation while IHC showed an increase of CRL substrates CDT1 and NRF-2. Regulation of all PD markers was dose and time dependent. Substrate levels were most robust in the highest dose groups and peaked between 2–8 hours after dosing, returning to base line levels by 24 hours. The MLN4924-NEDD8 adduct was observed in xenograft tumors within 30 minutes of treatment indicating that MLN4924 rapidly distributed to the tumor tissue and persisted up to 24 hours. These data supported the selection of a 3–6 hr window for post-dose biopsy sampling in the clinical studies. IHC assays were successfully adapted to clinical trial fine needle tumor biopsies and skin punch biopsies. In phase I studies levels of CDT1, NRF-2 and MLN4924-NEDD8 adduct in skin and tumor were compared in biopsies obtained at screening and 3–6 hours after the second day of dosing. CDT1 and NRF-2 IHC staining was quantified exclusively in regions of tumor or skin epidermal area. Elevations in CDT1 and NRF-2 substrate levels were observed in skin and tumor biopsies. Greater than 50% of all skin (n=38) and tumor biopsies (n=16) demonstrated a robust PD response suggesting target engagement. IHC analysis of MLN4924-NEDD8 adduct showed that drug was present in 100% of the post dose tumor biopsies. These data demonstrate evidence of inhibition of NAE activity and downstream pathway modulation by MLN4924 in skin and multiple tumor types. 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 A38.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-A38
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    Abstract CT303: A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. CT303-CT303
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. CT303-CT303
    Abstract: Background: Preclinical work showed improved anticancer efficacy with the combination of an mTOR and a PI3K inhibitor over either agent alone. We conducted a phase I study to determine the recommended phase II dose (RP2D) of the combination of everolimus (E), an mTOR inhibitor and buparlisib or BKM120 (B), a pan-PI3K inhibitor. Methods: Patients with advanced solid malignancies who have exhausted standard treatment options were enrolled. Main eligibility criteria include ECOG performance status 0-2, adequate end organ function and absence of glucose intolerance, uncontrolled hepatitis, anxiety or depression. Dose escalation was performed using a Bayesian Escalation with Overdose Control (EWOC) design to evaluate different doses of E (5mg or 10mg) and B (20, 40, 60 and 80 mg,) once daily continuously. Eligible patients were enrolled in cohorts of 3 patients. Pharmacokinetic (PK) assessment was conducted in cycle 1 on day 8 using peripheral blood samples collected at time 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours and prior to dosing on cycle 1 D day 15. Pharmacodynamic (PD) impact on mTOR/PI3K pathway modulation was evaluated in skin punch biopsies collected at baseline and at end of cycle 1. Results: We enrolled 35 patients: Median age 63yrs (range:40-79), 21 females (58%); 2 Latinos (6%), 7 Blacks (20%) and 26 Caucasians (74%); with cancers of the lung (8), colorectal (7), sarcomas (3), salivary gland (3), breast (3), thyroid (3), thymic (2), bladder (2), ovarian (2), head and neck (1) and PNET (1). The safety of 6 different dose combinations of E and B (5/20; 10/20; 5/40; 5/60; 10/60; 5/80) was assessed. The most frequent toxicities were: hyperglycemia, diarrhea, nausea, fatigue and AST elevation. The dose limiting toxicities observed in 6 patients were: fatigue (3), hyperglycemia (1), mucositis (1), acute renal failure (1) and urinary tract infection (1). The 5/60 combination was defined as the RP2D. The median number of cycles completed was 2 (range: 0-20). Of the 25 patients evaluable for efficacy, 8 (32%) had disease progression while 17 (68%) achieved stable disease (SD). Median duration of SD was 18 weeks (range: 2-83) and 7 patients had SD lasting ≥6 months. Steady-state PK data for both agents in 24 evaluable patients showed no evidence of drug-drug interaction, with dose-normalized maximum concentrations (Cmax) and area-under-the-curve (AUC0-∞) values for E and B in combination being comparable to single agent data. Preliminary signal of efficacy for the combination was observed in patients with thymic, breast and lung cancer. PD analysis is ongoing and will be presented at the meeting. Conclusion: The safety profile of the combination of everolimus plus buparlisib is well tolerated and the RP2D is 5mg/day and 60mg/day respectively on a continuous daily schedule. The efficacy data are encouraging and warrant further evaluation in phase II studies. Citation Format: Taofeek Kunle Owonikoko, R.Donald Harvey, Colleen Lewis, Zhengjia Chen, John S. Kauh, Meredith Renfroe, Rijalda Deovic, Gabriel L. Sica, Bradley C. Carthon, Wayne Bernard Harris, Bassel F. El-Rayes, Suresh S. Ramalingam, Fadlo R. Khuri. A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors. [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 CT303. doi:10.1158/1538-7445.AM2015-CT303
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-CT303
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
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    Abstract 2187: Pan-cancer identification and prioritization of cancer-associated differentially expressed genes: A biomarker discovery application
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2187-2187
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2187-2187
    Abstract: Cancer is fundamentally a disease of disordered gene expression. In fact, reversal or neutralization of the changes in gene expression has been shown to be attractive targets for the development of new anti-cancer drugs and therapeutic strategies. New approaches such as antibody drug conjugates (ADCs) also target differentially expressed genes as a mean to recognize tumor cells to selectively deliver toxins to a tumor. In the past decade, the global analysis of gene expression in human cancers have led to the development of a number of potential new biomarkers. For instance, mesothelin (MSLN) was identified as an over-expressed gene in pancreatic cancer and later was proved to be a useful diagnostic marker and so a therapeutic target. Large-scale gene expression analysis, using techniques such as RNA sequencing, provides a powerful tool to identify genes involved in human cancers. In this study, with the ultimate goal being to identify potential novel targets for cancer immunotherapy, we conducted a pan-cancer differential expression analysis in RNA sequencing data from more than 5,000 patients with 25 different cancer types generated by The Cancer Genome Atlas (TCGA). We identified differentially expressed genes (present in at least 5% of samples in a tumor type) in comparison to a large compendium of normal transcriptomes (more than 650 samples, including 30 tissue types) gathered from Genotype-Tissue Expression (GTEx), illumina BodyMap project 2.0, TCGA, and an in-house database. In total, we identified 892 putative tumor-associated differentially expressed genes. In order to further identify novel candidate genes and rank them based on their antigenic potential, we performed an extensive literature search and systematic review to collect the characteristics of an ideal tumor antigen (TA). We developed an Analytic Hierarchy Process (AHP) model - a multiple-criteria decision-making solution - to depict antigen properties for ranking and prioritizing the tumor-associated differentially expressed genes. Our model recognizes the known tumor antigens (such as CA9, Nectin-4, FN1, MSLN and MUC16, which are currently in clinic or pre-clinical studies) in the top 25 of the ranked list. We are currently validating the top-ranked novel antigens in an orthogonal panel of tumor and normal tissues and cell lines using PCR. Note: This abstract was not presented at the meeting. Citation Format: Daryanaz Dargahi, Richard D. Swayze, Leanna Yee, Peter J. Bergqvist, Bradley J. Hedberg, Alireza Heravi-Moussavi, Edie M. Dullaghan, Ryan Dercho, Christopher Bond, Jianghong An, John S. Babcook, Steven JM Jones. Pan-cancer identification and prioritization of cancer-associated differentially expressed genes: A biomarker discovery application. [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 2187. doi:10.1158/1538-7445.AM2015-2187
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-2187
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 6
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    Abstract 4919: Preclinical activity of SDX-7320 in mouse models of obesity and obesity-driven cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4919-4919
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4919-4919
    Abstract: Cancer patients who are obese face a greater risk of dying from cancer compared to nonobese patients (Calle, 2003). Obesity is believed to contribute to metastasis and progression of cancer via multiple mechanisms: increased secretion of the adipose tissue hormone leptin, decreased secretion of adiponectin, increased production of estrogen in adipose tissue, and elevated insulin (secondary to peripheral insulin resistance) as well as the local effects of inflammatory cytokines (Gucalp, 2016). Small-molecule inhibitors of methionine aminopeptidase type 2 (MetAP2) have previously demonstrated clinical activity in oncology (Kudelka, 1998) as well as obesity/type 2 diabetes (Hughes, 2013; Kim, 2015). However, development of some small-molecule MetAP2 inhibitors has been hampered by CNS side effects (Bhargava, 1999). SDX-7320 is a copolymer-drug conjugate of a novel fumagillin-derived MetAP2 inhibitor (SDX-7539) attached via a cleavable linker to a hydroxypropylmethacrylamide (HPMA) backbone, intended to limit CNS penetration and therefore reduce CNS toxicity. In vitro MetAP2 binding assays showed that SDX-7320 was unable to bind to MetAP2 while SDX-7539 was a potent binder (apparent IC50 = 0.13 nM), indicating that cleavage of SDX-7320 is required for biologic activity. SDX-7539 inhibited proliferation of human umbilical vein endothelial cells (HUVECs) with an apparent IC50 = 0.2 nM. The preclinical efficacy of SDX-7320 was evaluated in mouse models of obesity/insulin resistance and also in syngeneic tumor models coupled with high fat diet-induced obesity (DIO)/metabolic dysfunction. Obesity and insulin resistance were induced in C57Bl/6 mice by feeding them a high-fat diet (HFD) for at least 12 weeks. SDX-7320 was dosed subcutaneously every 4 days (for 28 days) into DIO mice or control mice fed a low-fat diet. SDX-7320 caused significant reduction in body weight and fat mass in obese mice while also reversing insulin resistance relative to controls. In addition, SDX-7320 caused greater reduction in body weight in obese mice relative to lean mice. Circulating levels of leptin and insulin were reduced while levels of adiponectin were increased in response to SDX-7320. In mouse models of obesity-accelerated tumor growth, SDX-7320 was more efficacious in obese relative to lean mice harboring subcutaneous B16F10 melanoma or EO771 mammary gland tumors. These effects occurred without any signs of neurotoxicity. SDX-7320, currently in phase I (solid tumors; all-comers; NCT02743637), is being developed for the treatment of cancers whose progression is accelerated in the setting of obesity and host metabolic dysfunction, termed “metabo-oncology.” Citation Format: Peter Cornelius, John S. Petersen, Benjamin Mayes, David Turnquist, Kimberly Sullivan, Alfred Anderson-Villaluz, Robert Lutz, Sara Little, Andrew Slee, Bradley J. Carver, James Shanahan. Preclinical activity of SDX-7320 in mouse models of obesity and obesity-driven cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4919.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-4919
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
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    Abstract CT153: SDX-7320 elicits improvements in tumor-related and metabolic biomarkers: Results of a phase 1 dose-escalation study in patients with advanced refractory or late-stage solid tumors
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT153-CT153
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT153-CT153
    Abstract: Background and Rationale: Metabo-oncology is the study of specific tumor types whose growth and/or metastasis is accelerated by metabolic dysfunction, often associated with hyper-adiposity. In this setting the metabolic hormones leptin, adiponectin and insulin are potential mediators. SDX-7320 is a novel methionine aminopeptidase type 2 inhibitor (MetAP2) being developed for use in combination with other anti-cancer agents to treat the metabo-oncology patient population. Study Design: This first-in-human study used a 3+3 design with dose expansion at the RP2D. Measurements included standard assessments of safety, tolerability, as well as inhibition of MetAP2 in whole blood, plasma levels of protein biomarkers and drug exposure. Tumor response was measured using RECIST v.1.1. Results: 32 patients with an average of 5.3 prior treatment regimens were dosed. Sub-cutaneous dosing of SDX-7320 began at 1.7 mg/m2 once per week (Q7D, 28 days/cycle) and was escalated to 49 mg/m2. Repeated Q7D administration at 49 mg/m2 resulted in dose-limiting (G3-G4) thrombocytopenia. Expansion at 49 mg/m2 confirmed thrombocytopenia as the dose-limiting toxicity (DLT), reversible upon cessation of dosing. Dose-escalation was re-initiated at 36 mg/m2 every two weeks (Q14D). Repeated dosing at 65 mg/m2 (Q14D) resulted in G3 reversible thrombocytopenia. Expansion at 49 mg/m2 (Q14D) confirmed that this was the maximum tolerated dose (MTD) on a Q14D schedule. No deaths or Grade 5 TEAEs attributable to SDX-7320 were reported. Six patients had a combined total of 9 Grade 3/4 TEAEs considered by the Investigator to be at least possibly SDX-7320-related: thrombocytopenia (4 patients) and single cases of anemia, anorexia, fatigue, QTc prolonged, and vasculitis. Fourteen patients (44% had stable disease & gt2 cycles and three patients had stable disease for ≥6 cycles. Inhibition of MetAP2 in whole blood was 100% at all doses evaluated while the time to reach 100% inhibition was inversely related to dose. When stratified for elevated baseline levels, the following biomarkers declined after initiating SDX-7320 (average of each patient's maximum % change relative to baseline +/- SD): bFGF (-53 +/- 76%), VEGF-C (-35 +/- 39%), and insulin (-55 +/- 30%). Without stratification, leptin levels declined (-51 +/-29%) and levels of adiponectin increased after SDX-7320 (+74 +/- 63% relative to baseline). Conclusions and Next Steps : SDX-7320 was well-tolerated with prolonged stable disease in an open-label, phase I first-in-human study. Improvements were observed in both tumor-related and metabolic biomarkers. Additional studies of SDX-7320 (in combination with other anti-cancer agents) in patients with solid tumors sensitive to metabolic hormones are scheduled. SDX-7320 is the first novel agent in clinical development to treat the metabo-oncology patient population. Citation Format: Monica M. Mita, Johanna Bendell, Alain C. Mita, Michael Gordon, Jasgit Sachdev, Bradley J. Carver, James Shanahan, Benjamin Mayes, Kris Awerkamp, David Browning, Neal Salomon, Kimberly Sullivan, Alfred Anderson-Villaluz, Joe Johnson, John S. Petersen, David J. Turnquist, Peter Cornelius. SDX-7320 elicits improvements in tumor-related and metabolic biomarkers: Results of a phase 1 dose-escalation study in patients with advanced refractory or late-stage solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT153.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-CT153
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    Abstract GS4-03: Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in a meta-analysis of three randomized controlled trials of breast conserving surgery +/- radiotherapy
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. GS4-03-GS4-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. GS4-03-GS4-03
    Abstract: Background: There are currently no commercially available tests to identify early stage breast cancer patients treated with breast conserving surgery (BCS) and systemic therapy at low risk of locoregional recurrence (LRR) for whom postoperative radiotherapy (RT) may be safely omitted. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify invasive breast cancer patients who may be candidates for RT omission after BCS. In this work, we seek to validate POLAR in a meta-analysis of three RCTs of BCS +/- RT: SweBCG91RT, Scottish Conservation Trial (SCT) and Princess Margaret Hospital (PMH). Methods: A patient-level meta-analysis was performed in 623 node-negative breast cancer patients with ER+/HER2-negative tumors who were enrolled in the three RCTs and for whom primary tumor material was available for analysis. Contributions from each cohort were as follows: SweBCG91RT N=354 (57%), SCT N=137 (22%), and PMH N=132 (21%). Numbers of LRR events in each cohort were as follows: SweBCG91RT N=72 (20%), SCT N=28 (20%), and PMH N=16 (12%). There was a mix of systemic therapy used (no systemic therapy for SweBCG91RT, chemotherapy or adjuvant endocrine therapy, but not both, in SCT, and tamoxifen but no chemotherapy for PMH). Median follow-up time for the patients who did not have LRR was 13.3 years for SweBCG91RT, 21.1 years for SCT, and 8.6 years for PMH. A multivariable Cox proportional hazards model on time to LRR, including the continuous standardized POLAR score, RT, and interaction, stratified by cohort, was used to test the interaction between the continuous POLAR score and RT. Additional Cox models tested the association between treatment arms separately for patients with a low and high POLAR score using a pre-specified cut point. Cumulative incidences were computed, with distant metastasis and death without recurrence considered as competing events. Results: The test for interaction between RT treatment and POLAR was statistically significant (p = 0.022). Patients with a high POLAR score (N=429 [69%]) had a large benefit from RT (10-year cumulative incidence of LRR: 20% [15%-26%] for those not treated with RT vs 7% [4%-11%] for those treated with RT; hazard ratio for RT vs no RT: 0.37 [0.23-0.60] , p & lt; 0.001), whereas there was no evidence of benefit from RT for patients with a low POLAR score (N=194 [31%], 10-year cumulative incidence of LRR: 5% [2%-11%] for those not treated with RT vs 7% [3%-14%] for those treated with RT; hazard ratio for RT vs no RT: 0.92 [0.42-2.02] , p = 0.832). Conclusions: To our knowledge, POLAR is the first genomic classifier that is not only prognostic for LRR but also predictive, showing a significant interaction between RT and the classifier. Patients with a high POLAR score should be recommended radiotherapy while patients with a low score may be candidates for omission of radiotherapy after breast conserving surgery. Citation Format: Per Karlsson, Anthony Fyles, S. Laura Chang, Bradley Arrick, Frederick Baehner, Per Malmström, Mårten Fernö, Erik Holmberg, Martin Sjöström, Fei-Fei Liu, David A. Cameron, Linda J. Williams, John MS Bartlett, Joanna Dunlop, Jacqueline Caldwell, Joseph F. Loane, Elizabeth Mallon, Tammy Piper, Wilma J. Jack, Ian Kunkler, Felix Y. Feng, Corey W. Speers, Lori Pierce, John Bennett, Karen J. Taylor. Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in a meta-analysis of three randomized controlled trials of breast conserving surgery +/- radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-03.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-GS4-03
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract P4-02-12: Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in early-stage invasive breast cancer patients of the Scottish Conservation Trial
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P4-02-12-P4-02-12
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P4-02-12-P4-02-12
    Abstract: Background: Adjuvant whole breast radiotherapy (RT) is provided to almost all women with early-stage invasive breast cancer after breast conserving surgery and appropriate systemic therapy. While there is increasing interest to personalize the use of RT based on molecular profiling, to date, there is no molecular signature available to reliably assess the benefit of radiotherapy after surgical resection. Here we assess the ability of a 16-gene signature named Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) to identify who may be suitable candidates for radiotherapy omission in patients of the Scottish Conservation Trial. Methods: The POLAR signature was applied to archival tissue from the Scottish Conservation Trial, which randomized 585 patients with stage I-II breast cancer, tumor size & lt; 4 cm, and age ≤70 years old to receive RT or not. The archival tissue was measured for ER (ER+ & gt;10%), PgR (PgR+ ≥20%), Ki67 (Ki67 high ≥14%), and HER2 (HER2+ defined as HER2 over-expressed or amplified). 26% received adjuvant chemotherapy, the remainder received tamoxifen 20 mg/daily for 5 years. Cox models for the locoregional recurrence (LRR) endpoint tested the association between treatment arms separately for patients with a low and high POLAR score using a pre-specified cut point. Cumulative incidences were computed, with distant metastasis and death without recurrence considered competing events. Results: 224 patients had tissue available and complete clinical data for analysis, 40 (18%) were node-positive. The distribution of clinicopathologic variables between the RT and no RT arms remained balanced. 43% were ER+/PgR+/Ki67 low/HER2-, 31% were ER+/HER2-/Ki67 high or PgR-, 5% were HER2+, and 13% were triple negative. The continuous standardized POLAR score was prognostic for LRR in the no RT arm after adjusting for relevant covariates (HR=1.78 [1.20-2.64], p=0.003). For patients with a POLAR-high score, the 10-year LRR rate was 31% [21%-42%] for patients not receiving RT and 8% [3%-15%] for patients receiving RT (HR 0.36 [0.19-0.69] , p=0.0022). For patients with a POLAR low score, the 10-year LRR rates were 20% [10%-33%] for patients not receiving RT and 6% [1%-18%] for patients receiving RT; HR=0.28 [0.08-0.98], p=0.046). In the subgroup of node-negative patients with ER+/HER2-negative tumors (N=137), there was a statistically significant RT benefit for patients with a POLAR high score (HR=0.31 [0.11-0.88] , p=0.028) but not for patients with a POLAR low score (HR=0.5 [0.1-2.4], p=0.39). Conclusions: For patients with early-stage invasive breast cancer treated with breast-conserving surgery without RT, POLAR is prognostic for LRR and may refine the selection of “low risk” for omission of RT. Citation Format: Karen J. Taylor, John MS Bartlett, John Bennett, S. Laura Chang, Bradley Arrick, Frederick Baehner, Joseph F. Loane, Tammy Piper, Elizabeth Mallon, Joanna Dunlop, Wilma J. Jack, Jacqueline Caldwell, Ian Kunkler, Linda J. Williams, Corey W. Speers, Felix Y. Feng, Lori Pierce, David A. Cameron. Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in early-stage invasive breast cancer patients of the Scottish Conservation Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-12.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P4-02-12
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    A Cathepsin-Targeted Quenched Activity–Based Probe Facilitates Enhanced Detection of Human Tumors during Resection
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 17 ( 2022-09-01), p. 3729-3741
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 17 ( 2022-09-01), p. 3729-3741
    Abstract: Fluorescence-guided surgery using tumor-targeted contrast agents has been developed to improve the completeness of oncologic resections. Quenched activity–based probes that fluoresce after covalently binding to tumor-specific enzymes have been proposed to improve specificity, but none have been tested in humans. Here, we report the successful clinical translation of a cathepsin activity–based probe (VGT-309) for fluorescence-guided surgery. Experimental Design: We optimized the specificity, dosing, and timing of VGT-309 in preclinical models of lung cancer. To evaluate clinical feasibility, we conducted a canine study of VGT-309 during pulmonary tumor resection. We then conducted a randomized, double-blind, dose-escalation study in healthy human volunteers receiving VGT-309 to evaluate safety. Finally, we tested VGT-309 in humans undergoing lung cancer surgery. Results: In preclinical models, we found highly specific tumor cell labeling that was blocked by a broad spectrum cathepsin inhibitor. When evaluating VGT-309 for guidance during resection of canine tumors, we found that the probe selectively labeled tumors and demonstrated high tumor-to-background ratio (TBR; range: 2.15–3.71). In the Phase I human study, we found that VGT-309 was safe at all doses studied. In the ongoing Phase II trial, we report two cases in which VGT-309 localized visually occult, non-palpable tumors (TBRs = 2.83 and 7.18) in real time to illustrate its successful clinical translation and potential to improve surgical management. Conclusions: This first-in-human study demonstrates the safety and feasibility of VGT-309 to label human pulmonary tumors during resection. These results may be generalizable to other cancers due to cathepsin overexpression in many solid tumors.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-1215
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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