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  • American Association for Cancer Research (AACR)  (14)
  • 2020-2024  (14)
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  • American Association for Cancer Research (AACR)  (14)
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  • 2020-2024  (14)
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  • 1
    Online Resource
    Online Resource
    Abstract 3006: Anticancer and multidrug resistance-reversing activities of novel antimicrobial peptides
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3006-3006
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3006-3006
    Abstract: Cancer is a growing concern in public health problems worldwide. Although the development of advanced chemotherapies has already partly reduced the cancer death rate and improved patients' prognosis, the phenomenon of multidrug resistance (MDR), which impairs the efficacy of a serial structure-unrelated anticancer agent, casts a large shadow over the bright future of chemotherapies. MDR has various mechanisms to induce acquired drug resistance of cancer cells after a relatively long period of chemotherapy. One of the most common causes of MDR is the expression of ATP-binding cassette (ABC) transporters, which act as efflux pumps on cancer cell membranes and transport anticancer drugs out of cancer cells thereby reducing the intracellular drug concentration. The growing resistance of cancer cells to current anticancer drugs leads to the urgent need to develop anticancer drugs with a new mechanism of action. Over the past decade, antimicrobial peptides have entered the view of scientists as a new generation of anticancer drugs. In this study, the anticancer effects and the reversal activities against ABC transporter mediated MDR of four novel antimicrobial peptides were investigated. The results showed that, at non-toxic concentrations in vitro, peptides #7, #14, #22, and #24 significantly sensitized ABCB1- and ABCC1-overexpressing cell lines, including both drug-selected MDR cancer cell lines and ABCB1 or ABCC1 gene transfected HEK293 cell lines, to the substrate anticancer drugs paclitaxel and vincristine. Among the antimicrobial peptide compounds, #14 and #24 with the most potent reversal ability were selected for further investigation. These peptides increased the intracellular accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells and that of [3H] -vincristine in ABCC1 overexpressing cells by suppressing the efflux function of ABCB1 and ABCC1 transporters, without causing alteration in the expression levels and localization patterns of ABCB1 and ABCC1 in overexpressing cells. Furthermore, the results of the ATPase assay showed that both two peptides stimulated ABCB1 ATPase activity. Taken together, these results demonstrated that peptide #14 and #24 reverse ABCB1- and ABCC1-mediated MDR through blocking the function of ABCB1 and ABCC1 without affecting the transporters' expression and cellular localization, which suggests that antimicrobial peptides may be used as a novel prospective cancer therapeutic strategy in the combination with traditional anticancer agents. Citation Format: Qiu-Xu Teng, Zi-Ning Lei, Xiaofang Luo, Jing-Quan Wang, Zuodong Qin, John N. Wurpel, Zhe-Sheng Chen. Anticancer and multidrug resistance-reversing activities of novel antimicrobial peptides [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 3006.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3006
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 2
    Online Resource
    Online Resource
    Abstract 5183: The preclinical characterization of TST001, a novel humanized anti-claudin18.2 mAb with enhanced binding affinity and anti-tumor activity
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5183-5183
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5183-5183
    Abstract: Claudin-18 isoform 2 (CLDN18.2) is a member of the human claudin family of tetraspan membrane proteins that are crucial structural and functional components of tight junctions. Unlike other family members, CLDN18.2 expression is strictly limited to differentiated epithelial cells of gastric mucosa. Interestingly CLDN18.2 was ectopically expressed at a significant level in multiple tumor types including gastric, esophageal, pancreatic and lung cancers, which makes it as an attractive anti-cancer target. TST001 is a novel humanized IgG1 monoclonal antibody, which specifically binds to cells expressing human CLDN18.2 with high affinity but not to the closely related Claudin 18.1. TST001 can compete with IMAB362, the clinical stage anti-CLDN18.2 mAb, for its binding to CLDN18.2 yet engages distinct epitope for binding. By reducing fucosylation during cell culture process, TST001 has further enhanced binding affinity to FcγRIIIa, which translates into more potent ADCC activity. Indeed, TST001 showed sub-nanomolar ADCC activity against gastric cancer cells expressing medium to low CLDN18.2 in the presence of human PBMC and NK cells, which is significantly more potent than IMAB362. TST001 also showed more potent CDC and ADCP activities against CLDN18.2 expressing cells than IMAB362. In both Sprague Dawley Rat and Cynomolgus Monkey, the systemic exposure of TST001 increased proportionally in a dose-dependent manner. In gastric cancer cell line and patient derived xenograft tumor models, TST001 showed more potent anti-tumor activity as compared with IMAB362. Furthermore, the combination of TST001 with chemo agents resulted in synergistic anti-tumor effect in these tumor models. In addition, we have also generated and characterized an antibody that is suitable for IHC based detection and is selective to CLDN18.2 over CLDN18.1. Altogether, these preclinical findings warrant further clinical evaluation of TST001 in patients with CLDN18.2 positive tumors. Citation Format: Fei Teng, Yi Gu, Hui Chai, Huanhuan Guo, Hongjun Li, Xiwen Wu, Xinlai Yao, Fei Xu, Lei Shi, Zhenzhi Yan, Xiaoli Zi, Zheng Dai, Timethy Liao, Lisa Zheng, Francis Fan, Zhen Li, Jerry Yang, Xueming Qian. The preclinical characterization of TST001, a novel humanized anti-claudin18.2 mAb with enhanced binding affinity and anti-tumor activity [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 5183.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5183
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    Abstract LB154: A potent human CAR NK cell therapy directed against pancreatic cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB154-LB154
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB154-LB154
    Abstract: Pancreatic cancer (PC) is one of the most lethal forms of cancer with a 5-year overall survival rate of 9%, routinely presenting as a late-stage incurable cancer that responds only modestly to standard chemotherapy. It is the third leading cause of cancer-related deaths. Approximately 60-80% of PC express prostate stem cell antigen (PSCA), as do gastric, bladder, prostate and some lung cancers. We therefore developed a chimeric antigen receptor (CAR) directed against PSCA for transduction into human natural killer (NK) cells. NK cells spontaneously kill both liquid and solid tumors without regards to expression of MHC self-antigens. In vivo, human NK cells utilize endogenous IL-15 to develop, survive, expand and activate against tumor cells. We therefore incorporated a soluble (s), secretable form of IL-15 into the PSCA CAR construct itself, followed by transduction into human NK cells obtained from umbilical cord blood with ~50% transduction efficiency. Transduced NK cells expressed the CAR directed against PSCA and secreted measurable amounts of human IL-15 protein in vitro. The PSCA CAR NK cells could be expanded ex vivo over 1,000-fold in approximately 16 days and retain their expression and their capacity to specificity kill PSCA(+) tumor cell targets in vitro. Indeed, when directed against the PSCA(+) human pancreatic tumor cell line (Capan-1), PSCA CAR NK cells produced significantly greater TNFα (P & lt; 0.0001), IFNγ (P & lt; 0.0001), and CD107a (P & lt; 0.05), when compared to PSCA CAR NK cells against the PSCA(-) human pancreatic tumor cell line PANC-1. Moreover, we showed that the co-expression of sIL-15 with PSCA CAR NK cells significantly enhances their cytotoxic function against pancreatic tumor cells compared to PSCA CAR NK cells without expression of sIL-15 (P & lt; 0.01) determined by a real-time cytolysis assay (RTCA) over 3.5 days. Encouraged by these in vitro data, we developed a model of metastatic human pancreatic cancer in immunodeficient mice using the PSCA(+) Capan-1 cell line. Compared to NK cells only expressing sIL-15, repeated infusions of human PSCA CAR NK cells from a viably frozen source resulted in a significantly prolonged survival (P & lt; 0.001), including clearance of metastatic disease. In summary, our in vitro and in vivo studies utilizing viably frozen human PSCA CAR NK cells co-expressing sIL-15 demonstrate significant efficacy in prolonging survival against a human pancreatic tumor cell line without evidence of systemic toxicity, providing a rationale to move this novel form of cell therapy into the clinic for PSCA(+) solid tumors. Citation Format: Kun-Yu Teng, Anthony Mansour, Zhu Zheng, Lei Tien, Yi Zheng, Zhiyao Li, Jianying Zhang, Saul J. Priceman, Michael A. Caligiuri, Jianhua Yu. A potent human CAR NK cell therapy directed against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB154.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-LB154
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 4
    Online Resource
    Online Resource
    Abstract 2843: RN486, a Bruton’s tyrosine kinase inhibitor, reverses multidrug resistance in ABCG2-overexpressing cancer cells
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2843-2843
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2843-2843
    Abstract: Overcoming ATP-binding cassette subfamily G member 2 (ABCG2)-mediated multidrug resistance (MDR) has attracted the attention of scientists because one of the critical factors leading to MDR is the overexpression of ABCG2. Identification of novel chemotherapeutic reagents as inhibitors of ABCG2 has been considered an effective strategy. RN486, a Bruton’s Tyrosine Kinase (BTK) inhibitor, was discovered to potentially reverse ABCB1-mediated MDR. In this study, we reported that RN486 effectively antagonizes ABCG2-mediated MDR in cancer cells. Non-toxic concentrations of RN486 remarkably increased the sensitivity of ABCG2-overexpressing cancer cells to conventional anticancer drugs mitoxantrone and topotecan. The reversal mechanistic studies showed that RN486 increased the accumulation and decreased the efflux of ABCG2 substrate drug in ABCG2-overexpressing cancer cells. In addition, the inhibitory effect of RN486 on ABCG2-associated ATPase activity was also verified. Docking analysis indicated a strong binding between RN486 and ABCG2 transporter. Meanwhile, the AGCG2 subcellular localization and expression level were not altered by the treatment of RN486. Taken together, our studies suggest that RN486 can antagonize ABCG2-mediated MDR in cancer cells via interacting with ABCG2 and inhibiting the transporting function. RN486 could be potentially used in combination with chemotherapy against ABCG2-mediated MDR in cancers. Citation Format: Xing-Duo Dong, Qisi Lu, Yi-Dong Li, Qiu-Xu Teng, Zi-Ning Lei, Zhe-Sheng Chen. RN486, a Bruton’s tyrosine kinase inhibitor, reverses multidrug resistance in ABCG2-overexpressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2843.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-2843
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Online Resource
    Abstract 4000: A novel pegylated bispecific antibody-drug conjugate (P-BsADC) targeting Her2+ cancers with improved efficacy and therapeutic window
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4000-4000
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4000-4000
    Abstract: Despite the fact that ADCs improve the efficacy and target selectivity comparing to the non-specific small molecule cytotoxicity drugs in cancer treatment, traditional ADCs still suffer from many issues which include low tumor penetration and accumulation, inefficient internalization, undesired efflux of ADC from tumor cells, significant on-target off-tumor toxicity, Fc mediated uptake that results in off-target toxicity, limited extravasation across capillary walls due to big molecular size, poor diffusion into the tumor masses due to increased tumor interstitial fluid pressure, and the binding-site-barrier. To address these issues, we previously reported that the compound JY201, a Polyethylene Glycol (PEG)-based bispecific ADC (P-BsADC) targeting two epitopes of Her2, demonstrated advantages in tumor penetration, internalization efficiency, lysosome trafficking effectiveness, no Fc related toxicity, and better efficacy in tumor inhibition than transtuzumab deruxtecan (Ds-8201). Continuing from our previous study, here we further reveal that JY201 can penetrate the tumor deeply and distribute more homogeneously in entire tumor masses while Ds-8201 limits its diffusion to the regions very close to the blood vessels in the tumor. Furthermore, JY201 shows better efficacy than Ds-8201 in inhibiting tumors with low expression of Her2 in pdx (patient derived xenograft) and cdx models. In addition, JY201 can effectively inhibit tumors resistant to Ds-8201. In an in-vitro plasma stability test, JY201 demonstrated high stability in cynomolgus monkey and human serums. JY201 also has a biodistribution profile advocating better safety than Ds-8201 in tumor bearing mice. In the repeated-dosing toxicological study in Her2 transgenic mice, JY201 with the dose of 50mg/kg was well tolerated and did not induce any tissue/organ damage to the animals. Due to much shorter half-life (5 times shorter) in mice for PEGylated proteins than in primates, we expect JY201 will have much higher tolerated dose than the 50mg/kg in primates. In summary, the findings from this study provide solid preclinical evidence for JY201 to be developed further as an efficacious and safe clinical treatment for patients with Her2 positive cancers. Citation Format: Yu (Yvonne) Wen, Shuqiang Yin, Weidong Lyu, Yang Lei, Qiudong Zhuo, Zibin Wu, Bin Sun, Shuangyu Tan, Lidong Jiang, Teng Zhang, Bo Gao, Rui Xu, Yong Li, Liling Zheng, Shumin Liu, David (Dechun) Wu. A novel pegylated bispecific antibody-drug conjugate (P-BsADC) targeting Her2+ cancers with improved efficacy and therapeutic window. [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4000.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-4000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    Abstract 5264: Selective toxicity of MX-106-4C, a survivin inhibitor, in P-glycoprotein-mediated multidrug resistant colon cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5264-5264
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5264-5264
    Abstract: One of the major challenges in colon cancer chemotherapy is multidrug resistance (MDR), which is typically mediated by the overexpression of ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp, ABCB1, MDR1). A number of P-gp inhibitors have been developed, however, none of these compounds have improved chemotherapeutic efficacy due to undesirable pharmacokinetic profiles or adverse effects, resulting in limited clinical success. Therefore, alternative approaches are urgently needed to circumvent MDR cancer. In previous study, a series of synthesized analogs of MX-106, as anti-cancer drugs targeting survivin, exhibited collateral sensitivity (CS) effect to P-gp overexpressing MDR colon cancer cells as well as ABCB1 gene transfected cells, reflected by more than 10-fold cytotoxic effect in P-gp positive MDR cell lines compared to drug sensitive cell lines. Among the analogs, MX-106-4C was identified as the leading compound with the most potent selective toxicity to P-gp overexpressing cells. MX-106-4C-induced CS effect was observed in both intrinsic and acquired P-gp overexpressing colon cancer cells, which was only partially reversed with the presence of a P-gp inhibitor. Nevertheless, this CS effect was abolished in ABCB1-knockout cells, indicating that the selective cytotoxicity was P-gp expression dependent, but only partially related to P-gp function. Furthermore, we found that MX-106-4C did not significantly affect P-gp ATPase activity or drug accumulation and efflux in P-gp-overexpressing cells. In P-gp overexpressing colon cancer cells, short-term (up to 72 h) incubation of MX-106-4C significantly down regulated P-gp expression at transcriptional level but not protein level, whereas long-term (14 d) incubation of MX-106-4C significantly down regulated P-gp protein expression and re-sensitized MDR colon cancer cells to doxorubicin. These findings suggested an indirect interaction and regulation between MX-106-4C and P-gp. Further study revealed that the selective cytotoxic effects of MX-106-4C were associated with cell cycle arrest at G1 phase and apoptosis through the downregulation of CDK4. Overall, this study demonstrates that MX-106-4C selectively kills P-gp positive MDR colon cancer cells and indirectly regulates P-gp, which provides a clue for CS compound design and a novel strategy to obviate P-gp-mediated colon cancer MDR by re-sensitizing heterogeneous tumors with CS agents. Citation Format: Zi-Ning Lei, Zhongzhi Wu, Qiu-Xu Teng, Min Xiao, Wei Li, John N. Wurpel, Zhe-Sheng Chen. Selective toxicity of MX-106-4C, a survivin inhibitor, in P-glycoprotein-mediated multidrug resistant colon cancer [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 5264.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5264
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 7
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    An Oncolytic Virus Expressing IL15/IL15Rα Combined with Off-the-Shelf EGFR-CAR NK Cells Targets Glioblastoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13 ( 2021-07-01), p. 3635-3648
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13 ( 2021-07-01), p. 3635-3648
    Abstract: IL15 is a pleiotropic cytokine with multiple roles that improve immune responses to tumor cells. Oncolytic viruses (OV) specifically lyse tumors and activate immune responses. Systemic administration of IL15 or its complex with the IL15Rα and chimeric antigen receptor (CAR) natural killer (NK) cells are currently being tested in the clinic. Here, we generated a herpes simplex 1–based OV-expressing human IL15/IL15Rα sushi domain fusion protein (named OV-IL15C), as well as off-the-shelf EGFR-CAR NK cells, and studied their monotherapy and combination efficacy in vitro and in multiple glioblastoma (GBM) mouse models. In vitro, soluble IL15/IL15Rα complex was secreted from OV-IL15C–infected GBM cells, which promoted GBM cytotoxicity and improved survival of NK and CD8+ T cells. Frozen, readily available off-the-shelf EGFR-CAR NK cells showed enhanced killing of tumor cells compared with empty vector–transduced NK cells. In vivo, OV-IL15C significantly inhibited tumor growth and prolonged survival of GBM-bearing mice in the presence of CD8+ T cells compared with parental OV. OV-IL15C plus EGFR-CAR NK cells synergistically suppressed tumor growth and significantly improved survival compared with either monotherapy, correlating with increased intracranial infiltration and activation of NK and CD8+ T cells and elevated persistence of CAR NK cells in an immunocompetent model. Collectively, OV-IL15C and off-the-shelf EGFR-CAR NK cells represent promising therapeutic strategies for GBM treatment to improve the clinical management of this devastating disease. Significance: The combination of an oncolytic virus expressing the IL15/IL15Rα complex and frozen, ready-to-use EGFR-CAR NK cells elicits strong antitumor responses in glioblastoma.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-21-0035
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
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    Abstract 3451: XS-04: A first-in-class dual IRAK4/BTK inhibitor for the treatment of hematological malignancies
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3451-3451
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3451-3451
    Abstract: Bruton's tyrosine kinase (BTK), a critical mediator of B-cell receptor (BCR) signaling, is a validated therapeutic target found across multiple B-cell cancers. Though initially responding to treatment with a BTK inhibitor, many patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), or Waldenström macroglobulinemia (WM) eventually progressed and clinical responses to BTK inhibitors are often poor in diffuse large B-cell lymphoma (DLBCL) patients. These highlight the need to understand the resistance mechanisms and improve responses to BTK inhibitors. The serine/threonine protein kinase IRAK4 is a key modulator of MYD88, which is found to be mutated in various aggressive B-cell lymphomas, including DLBCL. As BCR signaling and MYD88 signaling converge downstream on NF-kB activation, which plays an essential role in proliferation and survival of lymphoma cells, blockade of the two signaling pathways presents a potential therapeutic strategy. Here, we investigated the pharmacokinetic properties and anti-tumor activity of XS-04, a first-in-class dual inhibitor targeting both IRAK4 and BTK, using preclinical models of DLBCL subtypes, including tumors resistant to BTK inhibitors. XS-04 showed potent inhibition of IRAK4 and BTK kinases, with IC50 values of 0.2 and 2.9 nM, respectively. Favorable pharmacokinetic properties were also seen across multiple non-clinical species. Using in vitro anti-proliferative assays, we found that XS-04 inhibited proliferation of various DLBCL cell lines with IC50s of 30 to 40 nM. Mechanistically, XS-04 suppressed NF-kB activity in DLBCL cells and in vivo xenograft tumors, as indicated by decreased phosphorylation of IkBa. Oral dosing of XS-04 in TMD8 xenograft model led to a dose-dependent inhibition of tumor growth, which was comparable to the inhibition shown by a combination of BTK and IRAK4 inhibitors. In addition, XS-04 treatment resulted in tumor regression in a patient-derived ibrutinib-resistant MCL xenograft model, without significant changes in body weight. XS-04, a first-in-class IRAK4/BTK dual inhibitor, shows broad anti-tumor activity across preclinical models of DLBCL subtypes, including tumors resistant to BTK inhibitors. These results support XS-04 as a therapeutic candidate for the treatment of hematological malignancies. An IND submission is planned for 2023. Citation Format: Chunyan Zhao, Jianfei Wang, Aiguo Liu, Xin Gao, Yanfen Teng, Lei Liu, Yang Zhang, Xiaohong Yu. XS-04: A first-in-class dual IRAK4/BTK inhibitor for the treatment of hematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3451.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3451
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 9
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    Abstract 2983: A synthetic derivative of 1,2,3-triazole-pyrimidine hybrid reverses multidrug resistance mediated by MRP7
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2983-2983
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2983-2983
    Abstract: Multidrug resistance protein 7 (MRP7) is an important member of ABC transporter superfamily and has been revealed to transport a wide range of chemotherapeutic agents including taxanes, epothilone B, vinca alkaloids, daunorubicin and etoposide. In our previous study, a 1,2,3-triazole-pyrimidine hybrid 25 was synthesized and found significantly reversing multidrug resistance (MDR) mediated by ABCB1. In this study, we evaluated the efficacy of compound 25 in reversing MDR mediated by MRP7 in vitro. The results showed that 25 significantly sensitized cells overexpressing MRP7 to anticancer drugs that are MRP7 substrates at 3 μ;;M. Mechanism study showed that 25 reversed MRP7-mediated MDR by increasing the intracellular accumulation of anticancer drugs and decreasing drug efflux, without altering protein expression level or intracellular localization. Ligand-protein interactions were also modeled by docking with homology MRP7 model. Since limited researches on synthetic MRP7 modulators have been published, our findings provide a valuable prototype for structures which have the potential to be used in combination with conventional anticancer drugs to overcome MDR-mediated by MRP7. Citation Format: Jing-Quan Wang, Zi-Ning Lei, Qiu-Xu Teng, Bo Wang, Li-Ying Ma, Hong-Min Liu, Zhe-Sheng Chen. A synthetic derivative of 1,2,3-triazole-pyrimidine hybrid reverses multidrug resistance mediated by MRP7 [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 2983.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2983
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
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  • 10
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    Abstract 6307: A novel pegylated bispecific antibody-drug conjugate (P-BsADCpb-adc) targeting cancers co-expressing PD-L1 and CD47
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6307-6307
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6307-6307
    Abstract: ADCs have demonstrated improved efficacy and target selectivity comparing to the non-specific small molecule cytotoxicity drugs in cancer treatment. Yet, in solid tumor therapies, effort for further improvement of efficacy and safety has been hindered by the poor tumor penetration of conventional IgG based ADC, low internalization efficiency, undesired efflux of ADC from tumor cells, narrow therapeutic window due to the on-target/off tumor and Fc induced toxicity, etc. To address those issues, we previously reported that the compound JY201, a Polyethylene Glycol (PEG)-based bispecific ADC (P-BsADC) targeting two epitopes of Her2, demonstrated advantages in tumor penetration, internalization efficiency, lysosome trafficking, no Fc related toxicity, and better efficacy in tumor inhibition than transtuzumab deruxtecan (Ds-8201). In this study, we reveal another novel pegylated P-BsADC (JY207) formed by site-specific conjugation of a bispecific single chain fusion protein targeting PD-L1 and CD47 with PEG-MMAE (a pegylated cytotoxic payload MMAE). As expected, the compound JY207 retains all the advantages that JY201 possesses. Furthermore, JY207 does not bind to human red blood cells, but preferentially binds to CD47/PD-L1 double positive tumor cells, thus reduces the possibility of on-target toxicities. In vitro cytotoxicity studies showed that JY207 has strong potencies in CD47/PD-L1 double positive tumor cells, while showing almost no killing effect to CD47 or PD-L1 single positive tumor cells. In CDX models and a PDX model of transplanted tumor tissues from lung cancer patients, the compound demonstrated excellent tumor inhibition at low doses. In an in vitro plasma stability test, JY207 displays high stability in cynomolgus monkey and human serums. Preliminary repeated-dosing toxicological study has found the maximum tolerated dose of JY207 in CD47/PD-L1 double transgenic mice is 50mg/kg. In vivo pharmacokinetics and toxicological studies of JY207 are being conducted in cynomolgus monkeys and are expected to show desirable results. All those findings in this study warrant JY207 as a promising candidate for the clinical development for patients with CD47/PD-L1 double positive cancers. Citation Format: Shumin Liu, Weidong Lyu, Shuqiang Yin, Yang Lei, Qiudong Zhuo, Liling Zheng, Bin Sun, Shuangyu Tan, Lidong Jiang, Teng Zhang, Bo Gao, Rui Xu, Dechang Huang, Yong Li, Zibin Wu, David Wu, Yvonne (Yu) Wen. A novel pegylated bispecific antibody-drug conjugate (P-BsADCpb-adc) targeting cancers co-expressing PD-L1 and CD47. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6307.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6307
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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