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  • American Association for Cancer Research (AACR)  (5)
  • 1
    Online Resource
    Online Resource
    Abstract 843: Assessment of high-dose radiation efficacy administered to patient-derived xenografts based on the genomic reclassification of endometrial carcinomas
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 843-843
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 843-843
    Abstract: Adjuvant treatment of patients with endometrial cancer (EC) is tailored to clinical-pathologic prognostic factors. Pelvic radiation therapy for stage I EC provides a highly significant improvement of local control, but without survival advantage, and the use of adjuvant radiotherapy (RT) is limited to patients with high-intermediate or high-risk factors. Due to a rising incidence rate of EC there is an immediate need to improve how adjuvant treatments are being selected. The exploration of four genomic clusters by The Cancer Genome Atlas (TCGA) Network provides molecular insights and opportunity to refine current management strategies. However, no prospective validation of the relationship between cluster-association and treatment response has been reported. In this study, we evaluated the therapeutic efficacy of high-dose rate (HDR) radiation on the basis of genomic clusters. Objectives: To evaluate treatment response of HDR radiation according to TCGA classification using a panel of endometrial cancer patient-derived xenografts (EC-PDXs). Methods: Thirty-two EC-PDXs upon histologic and genomic characterization were orthotopically transplanted and propagated. Subcutaneously grafted PDX were subjected to a PDX clinical radiation trial. Animals were placed under a lead shield for irradiation once tumors reached 150-200 mm3 and 7Gy of radiation was delivered weekly for three weeks. Two additional weeks were given to investigate potential tumor regrowth. Histologic evaluation was conducted upon necropsy. Results: The overall response rate was 78% (25/32), in which high-grade ECs exhibited increased sensitivity to radiation compared to low-grade ECs (overall response rate 89% for high-grade versus 62% for low-grade). Copy number high (CNH) EC-PDXs showed the best response rate (100%), microsatellite instable (MSI) lines responded moderately (73%), and copy number low (CNL) lines exhibited the lowest response rate (42.9%). Nonresponders were noted among CNL and MSI clusters featuring low-grade endometrioid histology. Further evaluation of the proliferation index confirmed that all responders had a & gt;90% decrease on H-score compared to the nonresponders, which either showed a slight decrease or no changes at all. Conclusions: This is the first radiation treatment study selecting candidates within a PDX clinical trial based on TCGA cluster affiliation. Our findings suggest that EC-PDXs categorized as CNH or with higher histologic grade seem more sensitive to radiotherapy. Therefore, special attention and reconsideration of treatment recommendation should be given to patients harboring tumors with MSI and CNL genomic features. Further studies towards the identification of biomarkers or additional subclusters within responders and nonresponders will benefit physicians and patients to direct therapy. Citation Format: Chieh-Hsiang Yang, David K. Gaffney, Elke A. Jarboe, Margit M. Janát-Amsbury. Assessment of high-dose radiation efficacy administered to patient-derived xenografts based on the genomic reclassification of endometrial carcinomas [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 843.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-843
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract 3232: Anticancer drug delivery utilizing a mucoadhesive hybrid gel for local regional gynecologic applications
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3232-3232
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3232-3232
    Abstract: Cervical cancer is one of the leading gynecological malignancies affecting women worldwide. Although surgical cytoreduction and systemic chemotherapy combined with radiation are standard therapies, accessibility to such treatment as well as nonspecific toxicity limit its efficacy. We hypothesize that the site-specific local application of anticancer drugs utilizing innovative delivery technologies will improve efficacy, reduce toxicity and provide cost-effective, accessible therapeutic options. To test this hypothesis, we developed a mucoadhesive, polymeric hybrid chitosan gel embedding drug containing alginate beads. An optimized gel was achieved by mixing 1% chitosan (w/v) with glycerol dissolved in acetic acid (AA) solution at a volume ratio of 1:2 or 1:3 (2% AA:glycerol). Alginate beads were formed by dropping alginate solution (2%, w/v) into various concentrations of CaCl2 solution. In testing swelling properties, dried alginate beads transforming into wet ones were capable of releasing the drug load. Beads obtained from 1% CaCl2 solution demonstrated optimal and stable swelling properties that were 40 times greater than other formulations. Such beads, loaded with cisplatin (CDDP) dissolved in 0.9% NaCl were prepared. The loaded CDDP concentration was confirmed by colorimetric assay with Sn2Cl2 after re-swelling of the dried beads. Drug loaded-beads contained an average of 0.2mg of CDDP per 10 mg of dried beads. There was a linear correlation (R2 = 0.92) between the swelling ratio of the alginate beads and the amount of CDDP released, allowing the ability to estimate CDDP concentration based on the swelling ratio. Drug-loaded dried alginate beads were placed into a chitosan solution resulting in a hybrid hydrogel. To test the feasibility of local application of the gel on a mucosal surface, we investigated the swelling and mucoadhesive properties on a 4cm2 section of mouse peritoneal sidewall. We confirmed the complete swelling of beads within the hybrid gel suggested sufficient release of CDDP from the beads onto a biological surface. Mucoadhesive properties and toxicity were evaluated in vivo by surgically placing a 1cm2 sized gel pellet into the left peritoneal sidewall of immune competent female mice. The hybrid gel remained in place for 72 hours exhibiting no signs of local inflammation, tissue damage or systemic toxicity. Our results strongly suggest the feasibility of application of this hybrid gel to various mucosal surfaces. Ongoing experiments will evaluate the efficacy and safety of our hybrid gel/CDDP as a radiation enhancer in the treatment of cervical cancer and for the treatment of cervical dysplasia. 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 3232. doi:10.1158/1538-7445.AM2011-3232
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3232
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    Abstract 1756: Genomic reclassification of endometrial carcinoma predicts drug response and facilitates refinement of current management based on PDX-guided efficacy outcomes
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1756-1756
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1756-1756
    Abstract: Endometrial cancer (EC) is the most common gynecological malignancy among American women. Steadily increasing numbers of newly diagnosed cases and deaths emphasize the necessity of improving current management strategies. Rather than the commonly known two types of EC based on histological classification, the Cancer Genome Atlas (TCGA) Research Network recently reported a reclassification that categorizes EC into four subtypes based on genomic characterization. Molecular similarities between these subtypes and other cancers, including colorectal, ovarian, and breast cancers, were identified. But to date, no prospective validation has delivered an improved understanding on how to translate these findings to the clinic in the form of treatments adapting genomic guidance. Objectives: To evaluate drug response according to TCGA classification using a panel of twenty-seven established endometrial cancer patient-derived xenografts (EC-PDXs). Methods: Twenty-seven EC-PDXs representing various stages of disease and histological subtypes were orthotopically transplanted and propagated over multiple generations. Upon thorough characterization including histology, metastatic status, and molecular features, EC-PDXs were further categorized into the four TCGA molecular subtypes on the basis of somatic copy number variations (CNV), microsatellite instability (MSI), and POLE mutations. A PDX clinical trial (PCT) was performed to re-evaluate current standard treatments in comparison to therapeutic agents adopted from treatment regimens for other cancer types based on their molecular similarities. Results: EC-PDXs established from patients with recurrent disease exhibited minimal activity to first-line chemotherapeutic drugs, as expected, but remained sensitive to other second-line drugs. None of the tested drugs exhibited sufficient activity in POLE EC-PDXs. MSI EC-PDXs were found to be less sensitive to platinum-based treatment and resistant to 5-FU as reported for MSI colorectal cancer. CNV-high EC-PDXs were more sensitive to drugs adopted from current ovarian and breast cancer treatment regimens. Conclusions: This is the first study that demonstrates the utility of TCGA classification for treatment guidance based on a PCT. Patients with recurrent and persistent disease are in desperate need of new therapeutic options. Our findings open up the possibility to utilize drugs which are currently used in the treatment of other cancers for the treatment of EC based on molecular similarities. In addition, this is the first study that successfully demonstrated the use of molecular classification to enable the prediction of drug response, and thus may facilitate the refinement of current EC management in a more precise and personalized way. Citation Format: Chieh-Hsiang Yang, David K. Gaffney, Theresa L. Werner, Elke A. Jarboe, Jason Gertz, Katherine E. Varley, Matthew Peterson, Margit M. Janat-Amsbury. Genomic reclassification of endometrial carcinoma predicts drug response and facilitates refinement of current management based on PDX-guided efficacy outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1756. doi:10.1158/1538- 7445.AM2017-1756
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-1756
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Abstract 5402: Tissue accumulation and toxicity of platinum released from a novel chitosan hybrid gel for intraperitoneal drug delivery
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5402-5402
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5402-5402
    Abstract: Attempted surgical removal of advanced stage peritoneal cancers is mostly insufficient and often fails in areas affected by disseminated disease. But the successful elimination of peritoneal surface spread is known to have a significant impact on patient survival. However, standard therapies such as surgical cytoreduction and systemic chemotherapy combined with radiation have only shown limited-efficacy, accessibility, and nonspecific toxicity as well as frequent development of multidrug resistance (MDR). To overcome those limitations, we previously reported about the development of a mucoadhesive, chitosan-hybrid gel (CS(BCDDP)) embedded with cisplatin (CDDP) containing alginate beads for intraperitoneal administration (# 1948, AACR 2012). Here we report additional results illustrating CDDP release from CS(BCDDP) at different pH in vitro, CDDP accumulation to genomic DNA (gDNA) isolated from tissues as well as toxicity data in vivo. To determine the amount of CDDP released from CS (BCDDP) in vitro, B50μgCDDP, CDDP-chitosan (CS50μgCDDP) and CS (B50μgCDDP) pellets (8 mm ø, 1.5 mm thickness) were prepared and placed into a 6 well plate containing 2 ml/well PBS (pH 6, 7, 7.4 and 8). Multiple samples were collected during the 24 h incubation (37°C, 100rpm) period. The majority (75%) of CDDP was successfully released from CS(BCDDP) within the first 2 h at pH 7.4 showing the rate of drug release to be inversely correlated with pH yielding a more rapid release under acidic pH conditions. To assess CDDP accumulation to gDNA, inductively coupled plasma mass spectrometry (ICP-MS) was performed with tissue samples obtained from the left peritoneal sidewall of female nu/nu mice 24 hours after treatment with CS50μgCDDP, CS(B50μgCDDP), intravenously (i.v.) CDDP(IV50μgCDDP) and intraperitoneal (i.p) CDDP (IP50μgCDDP), respectively. The results demonstrated a greater than three-time enhancement of CDDP-accumulation to the gDNA from CS(B50μgCDDP) when compared to CS50μgCDDP and IV50μgCDDP administration. In addition, CS(B50μgCDDP) showed similar levels of CDDP adduction compared to direct IP50μgCDDP administration. Moreover, assessment of CDDP accumulation in kidneys and blood 24 h following treatment with either IP50μgCDDP or CS(B50μgCDDP), demonstrated significantly decreased kidney toxicity from CS(B50μgCDDP) when compared to IP50μgCDDP. Our results, therefore strongly suggest that administration of this hybrid gel directly to mucosal surfaces such as the peritoneal cavity is feasible making it an advantageous, safe and non-toxic intraperitoneal drug delivery system for the treatment of disseminated peritoneal cancers such as advanced or recurrent ovarian cancer. Currently ongoing experiments are evaluating the efficacy and safety of our hybrid gel/CDDP in an orthotopic peritoneal cancer animal model. Citation Format: Sungpil Cho, Yongen Sun, Elke A. Jarboe, Andrew P. Soisson, Mark K. Dodson, David K. Gaffney, C.Mattew Peterson, Margit M. Janat-Amsbury. Tissue accumulation and toxicity of platinum released from a novel chitosan hybrid gel for intraperitoneal drug delivery. [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 5402. doi:10.1158/1538-7445.AM2014-5402
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-5402
    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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  • 5
    Online Resource
    Online Resource
    Abstract 1948: Tissue accumulation and release of platinum from a novel chitosan-hybrid gel after intraperitoneal drug delivery
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1948-1948
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 1948-1948
    Abstract: Gynecological malignancies such as cervical, endometrial and ovarian cancer still are the leading causes of death for women worldwide. However, standard therapies such as surgical cytoreduction and systemic chemotherapy combined with radiation have shown limited-efficacy by accessibility as well as nonspecific toxicity. To overcome those limitations, we previously reported about the development of a muco-adhesive, chitosan-hybrid gel (CS(BCDDP)) embedded with alginate beads containing cisplatin (CDDP) for a local, intraperitoneal application (# 3232, AACR 2011). Here we report the results of CDDP release from the (CS(BCDDP)), its cellular activity in vitro and CDDP accumulation to genomic DNA (gDNA) of tissues in vivo. To determine the amount of CDDP released from (CS(BCDDP)) in vitro, we used a colorimetric SnCl2 assay following the incubation in 0.9% NaCl solution for 24 hrs. (CS(BCDDP)) demonstrated successful release of 90% CDDP within 2 hrs and consistent CDDP-release could be maintained for up to 24 hrs. To test activity of CDDP released from (CS(BCDDP)), clonogenic assay was performed with Hela (human cervical adenocarcinoma) cells. Cells treated with (CS(BCDDP)) demonstrated a significantly low number of colonies, generating 9 (± 6) colonies per 500 cells seeded compared with 233 (± 10) colonies per 500 cells treated with an empty, no drug containing control gel (CS). To further assess CDDP accumulation to gDNA of tissues in vivo, inductively coupled plasma mass spectrometry (ICP-MS) was performed with tissue samples obtained from the left peritoneal sidewall of female nude mice following treatment with a control gel mixed with CDDP (CSCDDP), (CS(BCDDP)), and intravenously (i.v.) CDDP(CDDPIV). The results demonstrated a greater than three-time enhancement of CDDP-accumulation to the gDNA from (CS(BCDDP)) when compared to CDDPIV. Moreover, (CS(BCDDP)) also demonstrated higher accumulation of CDDP to gDNA when compared with CSCDDP. Relative values were 3.2 (±0.9) for (CS(BCDDP)) and 1.3 (± 0.4) for CSCDDP compared to values obtained from CDDPIV. Our in vitro and in vivo results, strongly suggest the feasibility of applying this hybrid gel locally to mucosal surfaces of the female reproductive tract and its advantage for intraperitoneal drug accumulation. Currently ongoing experiments are evaluating the efficacy and safety of our hybrid gel/CDDP in orthotopic endometrial, ovarian and cervical cancer animal models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1948. doi:1538-7445.AM2012-1948
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-1948
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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