Experimental and Molecular Therapeutics最新文献

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Abstract 1062: Inhibition of ovarian and endometrial cancer cell proliferation by an anti-ROR1 monoclonal antibody 摘要:抗ror1单克隆抗体对卵巢癌和子宫内膜癌细胞增殖的抑制作用

Experimental and Molecular Therapeutics

Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1062

Dongli Liu, G. Kaufmann, J. Breitmeyer, Kristie-Ann Dickson, D. Marsh, C. Ford

引用次数: 0

Abstract 1472: Novel EGFR WT sparing, HER2 selective inhibitors for the treatment of HER2 exon 20 insertion driven tumors address a clear unmet medical need 摘要:用于治疗HER2外显子20插入驱动型肿瘤的新型EGFR WT保留、HER2选择性抑制剂解决了一个明显未满足的医疗需求

Experimental and Molecular Therapeutics

Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1472

Ralph A. Neumüller, B. Wilding, D. Scharn, D. Böse, V. Santoro, D. Gerlach, P. Ettmayer, Thomas Gerstberger, Julian E. Fuchs, Matthias Treu, S. Zahn, A. Baum, P. Chetta, M. Pearson, D. McConnell, N. Kraut, Flavio Solca

引用次数: 1

Abstract 1016: A new biomarker in hematological malignancies 摘要1016:一种新的血液恶性肿瘤生物标志物

Experimental and Molecular Therapeutics

Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1016

T. Borgovan

引用次数: 0

Abstract 1229: Novel Arf1-targeting ã-dipeptides counteract triple negative breast cancer by inducing autophagic death 摘要1229:新型靶向arf1的<s:1> -二肽通过诱导自噬死亡来对抗三阴性乳腺癌

Experimental and Molecular Therapeutics

Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1229

Leilei He, A. Chavanieu, Yen Vo-Hoang, Yong Teng

引用次数: 1

Abstract 1404: Loss of adenomatous polyposis coli induces DOX resistance through upregulation of ABC transporters 摘要:大肠腺瘤性息肉病的丧失通过上调ABC转运蛋白诱导DOX抗性

Experimental and Molecular Therapeutics

Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1404

C. Stefanski, Jenifer R Prosperi, Lauren Milac

引用次数: 0

Abstract 1342: Development and preclinical evaluation of unique first-in-class small molecule inhibitors of the anti-apoptotic protein FLIP 1342:独特的抗凋亡蛋白FLIP小分子抑制剂的开发和临床前评估

Experimental and Molecular Therapeutics

Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1342

C. Higgins, J. Fox, Jamie Z. Roberts, D. Doherty, Trevor R. Perrior, R. Boffey, Tim Harrison, D. Longley

In cancer, evasion of cell death is a fundamental cause of resistance to therapy, prompting the development of therapeutics that reactivate cell death pathways such as Bcl-2 family inhibitors and IAP antagonists. The apoptosis modulator Cellular FLICE-like inhibitory protein (FLIP) is a non-redundant inhibitor of caspase-8 activation and is the only human pseudo-caspase. Caspase-8 is the initiator caspase for the extrinsic apoptotic pathway and is now recognized as the molecular “switch” that controls the 3 major forms of programmed cell death: apoptosis, necroptosis and pyroptosis. As such, methods to selectively activate caspase-8 in appropriate disease contexts represent an exciting new therapeutic paradigm. FLIP is frequently overexpressed in solid and haematological cancers where it is associated with poor prognosis and chemo- and radio-resistance. Moreover, by regulating caspase-8 activity, FLIP is a key determinant of cell death induced by death ligands such as TRAIL expressed by immune effector cells. Thus, targeting FLIP9s interaction with caspase-8 represents a unique therapeutic opportunity for enhancing standard-of-care anti-cancer therapies and promoting anti-tumor immunity.We report the discovery and characterisation of small molecule first-in-class selective inhibitors capable of disrupting FLIP9s interaction with procaspase-8 in human cancer cells. These small molecule inhibitors induce caspase-8-dependent cell death as single agents and dramatically enhance apoptosis induced by recombinant TRAIL and 2nd generation multivalent TRAIL-R2 agonists in the nM concentration range. KRAS mutant non-small cell lung cancer (NSCLC) was identified as a major sensitive disease setting for FLIP inhibitors with single digit nM activity in vitro in several models and single agent in vivo efficacy. FLIP inhibitors also demonstrated in vitro efficacy in combination with KRAS G12C inhibitors in KRAS G12C mutant NSCLC and in vitro and in vivo efficacy in combination with the 3rd generation EGFR inhibitor Osimertinib in EGFR mutant NSCLC. We have also observed single agency nM efficacy in lymphoma and leukemia models and significant efficacy in combination with standard-of-care chemotherapeutics in KRAS mutant colorectal and pancreatic cancers. In summary, we have identified novel FLIP-targeted activators of caspase-8 with a unique mechanism-of-action and the potential for use in the treatment of several human cancers and leukemias either as a single agent, or in combination with standard-of-care chemotherapeutics and other clinically-relevant targeted agents. AcknowledgementsThis work was supported by a Seeding Drug Discovery award from the Wellcome Trust. Citation Format: Catherine A. Higgins, Jennifer Fox, Jamie Roberts, Declan Doherty, Trevor Perrior, Ray Boffey, Tim Harrison, Daniel B. Longley. Development and preclinical evaluation of unique first-in-class small molecule inhibitors of the anti-apoptotic protein FLIP [abstract]. In: Proceedings o

在癌症中，逃避细胞死亡是对治疗产生耐药性的根本原因，这促使了重新激活细胞死亡途径的治疗方法的发展，如Bcl-2家族抑制剂和IAP拮抗剂。凋亡调节剂细胞flice样抑制蛋白(FLIP)是caspase-8激活的非冗余抑制剂，是唯一的人类伪caspase。caspase -8是外源性凋亡途径的启动caspase，现在被认为是控制3种主要程序性细胞死亡形式的分子“开关”:凋亡、坏死坏死和焦亡。因此，在适当的疾病环境中选择性激活caspase-8的方法代表了一种令人兴奋的新治疗范式。FLIP在实体癌和血液癌中经常过表达，与预后不良、化疗和放射耐药有关。此外，通过调节caspase-8活性，FLIP是免疫效应细胞表达的TRAIL等死亡配体诱导细胞死亡的关键决定因素。因此，靶向FLIP9s与caspase-8的相互作用为增强标准抗癌治疗和促进抗肿瘤免疫提供了独特的治疗机会。我们报道了在人类癌细胞中发现并鉴定了一类能够破坏FLIP9s与procaspase-8相互作用的小分子选择性抑制剂。这些小分子抑制剂作为单一药物诱导caspase-8依赖性细胞死亡，并在nM浓度范围内显著增强重组TRAIL和第二代多价TRAIL- r2激动剂诱导的细胞凋亡。KRAS突变型非小细胞肺癌(NSCLC)被确定为FLIP抑制剂的主要敏感疾病，在几种模型中具有个位数nM活性和单药体内疗效。FLIP抑制剂与KRAS G12C抑制剂联合治疗KRAS G12C突变型NSCLC也显示出体外疗效，与第3代EGFR抑制剂奥西替尼联合治疗EGFR突变型NSCLC也显示出体外和体内疗效。我们还观察到单药nM在淋巴瘤和白血病模型中的疗效，以及在KRAS突变的结直肠癌和胰腺癌中与标准治疗化疗药物联合使用的显着疗效。总之，我们已经确定了新的flip靶向caspase-8激活剂，具有独特的作用机制，并且可能用于治疗几种人类癌症和白血病，无论是作为单一药物，还是与标准治疗化疗药物和其他临床相关靶向药物联合使用。本工作得到了来自Wellcome Trust的种子药物发现奖的支持。引用格式:Catherine A. Higgins, Jennifer Fox, Jamie Roberts, Declan Doherty, Trevor Perrior, Ray Boffey, Tim Harrison, Daniel B. Longley。一类独特的抗凋亡蛋白FLIP小分子抑制剂的开发和临床前评估[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):1342。

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引用次数: 4

Abstract 1284: P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation 摘要1284:通过ATF4转录调控p53突变肿瘤p53通路的p53独立恢复

Experimental and Molecular Therapeutics

Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1284

X. Tian, N. Ahsan, W. El-Deiry

A long-term goal in the cancer-field has been to develop strategies for treating p53-mutated tumors. A novel small-molecule, PG3-Oc, restores p53 pathway-signaling in tumor cells with mutant-p53, independently of p53/p73. PG3-Oc partially upregulates the p53-transcriptome (13.7% of public p53 target-gene dataset; 15.2% of in-house dataset) and p53-proteome (18%, HT29; 16%, HCT116-p53-/-). Bioinformatic analysis indicates critical p53-effectors of growth-arrest (p21), apoptosis (PUMA, DR5, Noxa), autophagy (DRAM1), and metastasis-suppression (NDRG1) are induced by PG3-Oc. ERK1/2- and CDK9-kinases are required to upregulate ATF4 by PG3-Oc which restores p53 transcriptomic-targets in cells without functional-p53. PG3-Oc represses MYC (ATF4-independent), and upregulates PUMA (ATF4-dependent) in mediating cell death. With largely nonoverlapping transcriptomes, induced-ATF4 restores p53 transcriptomic targets in drug-treated cells including functionally important mediators such as PUMA and DR5. Our results demonstrate novel p53-independent drug-induced molecular reprogramming involving ERK1/2, CDK9, and ATF4 to restore upregulation of p53 effector genes required for cell death and tumor suppression. Citation Format: Xiaobing Tian, Nagib Ahsan, Wafik S. El-Deiry. P53-independent restoration of p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation [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 1284.

癌症领域的一个长期目标是开发治疗p53突变肿瘤的策略。一种新的小分子，PG3-Oc，在p53突变的肿瘤细胞中恢复p53通路信号，独立于p53/p73。PG3-Oc部分上调p53转录组(13.7%的公共p53靶基因数据集;15.2%的内部数据集)和p53-蛋白质组(18%，HT29;16%, HCT116-p53 - / -)。生物信息学分析表明，PG3-Oc可诱导生长停止(p21)、细胞凋亡(PUMA、DR5、Noxa)、自噬(DRAM1)和转移抑制(NDRG1)等关键p53效应物。ERK1/2-和cdk9激酶需要通过PG3-Oc上调ATF4, PG3-Oc在没有功能p53的细胞中恢复p53转录组靶标。PG3-Oc在介导细胞死亡过程中抑制MYC (atf4独立)，上调PUMA (atf4依赖)。由于转录组大部分不重叠，诱导atf4在药物处理细胞中恢复p53转录组靶点，包括功能重要的介质，如PUMA和DR5。我们的研究结果表明，新的p53独立药物诱导的分子重编程涉及ERK1/2, CDK9和ATF4，以恢复细胞死亡和肿瘤抑制所需的p53效应基因的上调。引用格式:Xiaobing Tian, Nagib Ahsan, Wafik S. El-Deiry。通过ATF4转录调控p53突变肿瘤中p53通路的p53非依赖性恢复[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):1284。

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引用次数: 0

Abstract 1109: A novel strategy to cope with osimertinib resistance in non-small cell lung cancer by treatment with a PIM kinase inhibitor in combination with a MERTK-selective kinase inhibitor 摘要:PIM激酶抑制剂联合mertk选择性激酶抑制剂治疗非小细胞肺癌应对奥希替尼耐药的新策略

Experimental and Molecular Therapeutics

Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1109

D. Yan, Z. Tan, Xiaodong Wang, S. Frye, H. Earp, D. DeRyckere, D. Graham

Osimertinib is currently the preferred treatment for EGFR-mutated non-small cell lung cancer (NSCLC) patients due to its superior therapeutic efficacy and prolonged overall survival compared to earlier generation EGFR tyrosine kinase inhibitors, but durable responses to osimertinib treatment are rare due to acquired drug resistance. Thus, there is an urgent need for novel strategies to treat osimertinib-resistant NSCLC. Recently, we found that treatment with MRX-2843, a novel MERTK-selective kinase inhibitor currently in Phase I clinical trials, resulted in dose-dependent inhibition of cell expansion and colony formation in an osimertinib-resistant (osiR) H4006 derivative cell line. An unbiased screen of 378 kinase inhibitors was carried out to identify compounds that synergized with MRX-2843 to inhibit expansion of an osiR derivative of the EGFR-mutated H4011 cell line. Treatment with 1µM PIM kinase inhibitor SGI-1776 or 100nM MRX-2843 alone reduced cell density by 5±3% and 44±7%, respectively, while treatment with MRX-2843 and SGI-1776 combined mediated an 82±0.4% decrease. Synergy was also observed in H4006 osiR and H1650 osiR derivative cell lines. Furthermore, treatment with PIM447, a structurally distinct PIM kinase inhibitor, and MRX-2843 decreased cell expansion more effectively than either agent alone. Mechanistically, treatment with a PIM kinase inhibitor in combination with MRX-2843 decreased downstream PI3K-AKT and MAPK-ERK signaling more effectively than single agents. Additionally, combined treatment with MRX-2843 and SGI-1776 prevented colony formation, while single agents had limited effect. In all, these data indicate that combining MRX-2843 and a PIM TKI may control osimertinib resistant tumor growth, providing a potential treatment strategy for osimertinib resistant EGFR-mutated NSCLC patients for whom the choices are still limited. Citation Format: Dan Yan, Zikang Tan, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, III, Deborah DeRyckere, Douglas K. Graham. A novel strategy to cope with osimertinib resistance in non-small cell lung cancer by treatment with a PIM kinase inhibitor in combination with a MERTK-selective kinase inhibitor [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 1109.

由于与早期EGFR酪氨酸激酶抑制剂相比，奥西替尼具有优越的治疗效果和更长的总生存期，因此目前是EGFR突变的非小细胞肺癌(NSCLC)患者的首选治疗方法，但由于获得性耐药，对奥西替尼治疗的持久反应很少。因此，迫切需要新的策略来治疗耐奥西替尼的非小细胞肺癌。最近，我们发现MRX-2843(一种目前处于I期临床试验的新型mertk选择性激酶抑制剂)对奥西替尼耐药(osiR) H4006衍生细胞系的细胞扩增和集落形成产生剂量依赖性抑制。对378种激酶抑制剂进行了无偏筛选，以确定与MRX-2843协同作用的化合物，以抑制egfr突变的H4011细胞系的osiR衍生物的扩增。1µM PIM激酶抑制剂SGI-1776或100nM MRX-2843分别使细胞密度降低5±3%和44±7%，而MRX-2843和SGI-1776联合处理使细胞密度降低82±0.4%。在H4006 osiR和H1650 osiR衍生细胞系中也观察到协同作用。此外，PIM447(一种结构独特的PIM激酶抑制剂)和MRX-2843联合治疗比单独使用任何一种药物更有效地降低了细胞扩增。从机制上讲，PIM激酶抑制剂与MRX-2843联合治疗比单一药物更有效地降低下游PI3K-AKT和MAPK-ERK信号。此外，MRX-2843和SGI-1776联合治疗可防止菌落形成，而单一药物的效果有限。总之，这些数据表明联合MRX-2843和PIM TKI可以控制奥西替尼耐药的肿瘤生长，为选择仍然有限的奥西替尼耐药egfr突变的非小细胞肺癌患者提供了一种潜在的治疗策略。引用格式:颜丹，谭子康，王晓东，Stephen V. Frye, H. Shelton Earp, III, Deborah DeRyckere, Douglas K. Graham。PIM激酶抑制剂联合mertk选择性激酶抑制剂治疗非小细胞肺癌应对奥希替尼耐药的新策略[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):1109。

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引用次数: 1

Abstract 1470: Preclinical activity of the first reversible, potent and selective inhibitor of EGFR exon 20 insertions 1470:首个可逆、有效和选择性EGFR外显子20插入抑制剂的临床前活性

Experimental and Molecular Therapeutics

Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1470

F. Siegel, S. Siegel, Keith Graham, Bethany Kaplan, K. Petersen, U. Boemer, U. Eberspaecher, D. Korr, Ursula Moenning, D. Suelzle, J. Schroeder, F. Prinz, S. Zitzmann-Kolbe, G. Karsli-Uzunbas, T. Lewis, M. Hermsen, A. Cherniack, F. Nussbaum, K. Eis, M. Meyerson, H. Greulich

引用次数: 3

Abstract 1180: A novel synthetic lethality treatment strategy for metastatic breast cancer 摘要:一种新的转移性乳腺癌合成致死性治疗策略

Experimental and Molecular Therapeutics

Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1180

Justin Zonneville, Mo Wang, Mohammed M. Alruwaili, K. Eng, T. Melendy, B. Park, R. Iyer, C. Fountzilas, Andrei V Bakin

Breast carcinomas commonly carry mutations in the tumor suppressor p53, while therapeutic efforts to target mutant p53 were largely unfruitful. Here we present preclinical data supporting a novel combination therapy strategy for treatment of p53-deficient cancers. Genomic data revealed a high expression activity of Base-Excision Repair (BER) pathways in p53-deficient breast cancers. However, we found that BER-mediated repair was significantly dysregulated in p53-mutant cancer cells. Treatment with deoxyuridine analogues induced accumulation of DNA damage in p53-mutant cells and inhibitors of poly (ADP-ribose) polymerase (PARPi) greatly enhanced this response. In contrast, normal cells responded to PARPi with activation of the p53-p21 axis and cell cycle arrest. Inactivation of either p53 or p21/CDKN1A in p53 wild-type cells conferred the p53-mutant phenotype. Preclinical breast cancer studies revealed that the combination of deoxyuridine analogue with PARPi was more effective in inhibition of tumor growth and metastases than either drug alone. This work illustrates a novel combination therapy strategy that may improve survival rates and outcomes for thousands of breast cancer patients. Citation Format: Justin Zonneville, Moyi Wang, Mohammed Alruwaili, Kevin Eng, Thomas Melendy, Ben Ho Park, Renuka Iyer, Christos Fountzilas, Andrei V. Bakin. A novel synthetic lethality treatment strategy for metastatic breast 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 1180.

乳腺癌通常携带肿瘤抑制因子p53突变，而针对突变p53的治疗努力在很大程度上是无效的。在这里，我们提出临床前数据支持一种新的联合治疗策略来治疗p53缺陷癌症。基因组数据显示，在p53缺失的乳腺癌中，碱基切除修复(BER)通路具有高表达活性。然而，我们发现在p53突变的癌细胞中，ber介导的修复明显失调。脱氧尿苷类似物在p53突变细胞中诱导DNA损伤积累，聚(adp -核糖)聚合酶(PARPi)抑制剂大大增强了这种反应。相比之下，正常细胞对PARPi的反应是p53-p21轴的激活和细胞周期阻滞。p53野生型细胞中的p53或p21/CDKN1A失活均可产生p53突变表型。临床前乳腺癌研究表明，脱氧尿苷类似物与PARPi联合使用比单独使用任何一种药物更有效地抑制肿瘤生长和转移。这项工作说明了一种新的联合治疗策略，可以提高数千名乳腺癌患者的生存率和预后。引用格式:Justin Zonneville, Moyi Wang, Mohammed Alruwaili, Kevin Eng, Thomas Melendy, Ben Ho Park, Renuka Iyer, Christos Fountzilas, Andrei V. Bakin一种新的转移性乳腺癌合成致死性治疗策略[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):1180。

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引用次数: 0

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