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Abstract 1363: Exposure-toxicity analysis of cabozantinib in patients with salivary gland cancer and renal cell cancer 1363:卡博赞替尼在涎腺癌和肾细胞癌患者中的暴露毒性分析
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1363
Stefanie D. Krens, W. V. Boxtel, M. Uijen, F. Jansman, I. Desar, S. Mulder, C. V. Herpen, N. P. Erp
{"title":"Abstract 1363: Exposure-toxicity analysis of cabozantinib in patients with salivary gland cancer and renal cell cancer","authors":"Stefanie D. Krens, W. V. Boxtel, M. Uijen, F. Jansman, I. Desar, S. Mulder, C. V. Herpen, N. P. Erp","doi":"10.1158/1538-7445.AM2021-1363","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1363","url":null,"abstract":"Background Cabozantinib is approved for treatment of renal cell cancer (RCC) in a starting dose of 60 mg. However, in the registration studies dose reductions were needed in 46-62% of patients due to toxicity. Improved clinical efficacy of cabozantinib was observed in RCC patients with an average exposure of > 750 ug/L. Data about cabozantinib pharmacokinetics in patients routinely treated with this drug is scarce, while treatment is challenging due to toxicity. Therefore, we explored the cabozantinib exposure in patients with two different tumour types in our clinic. Methods Clinical data and cabozantinib trough concentrations (Cmin) were collected from all patients treated with cabozantinib with at least one measured Cmin at steady state in our clinic between Jan 2018 - Aug 2020. We included salivary gland cancer (SGC) patients treated in a phase II study and RCC patients from our outpatient clinic. Geometric mean (GM) Cmin at the start dose, at 40 mg and at best tolerated dose (BTD) were compared between the two tumour types. Results In total 47 patients were included. All patients with SGC (n=22) started with 60 mg, while 13 of 25 patients with RCC started with 40 mg. GM Cmin level at the start dose was 1350 µg/L (95% CI 1182-1781) vs. 689 µg/L (95% CI 576-823) (P 750 ug/L. Conclusion Unexpectedly, cabozantinib levels were significantly higher in patients with SGC compared to those with RCC at the dose of 40 mg. However, cabozantinib levels at BTD were comparable between patients with SGC and RCC. At BTD, the majority of patients did not reach the target of >750 µg/L. For most patients with RCC, the cabozantinib level at BTD corresponded to a dose of 40 mg. Therefore, 40 mg instead of 60 mg as a starting dose followed by dose-adjustment based on exposure and tolerability may be preferred in patients with RCC. Although cabozantinib is not registered for SGC, an even lower starting dose of 20 mg/day may be required in these patients based on cabozantinib levels at BTD. Future studies should focus on identifying an optimal and tolerable exposure-response target value for cabozantinib and elucidate factors that contribute to the differences in exposure, in order to individualise and improve treatment. Citation Format: Stefanie D. Krens, Wim van Boxtel, Maike J. Uijen, Frank G. Jansman, Ingrid M. Desar, Sasja F. Mulder, Carla M. van Herpen, Nielka P. van Erp. Exposure-toxicity analysis of cabozantinib in patients with salivary gland cancer and renal cell 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 1363.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85543595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Abstract 1419: Small molecule inhibitor of NRF2 selectively overcomes sorafenib resistance in KEAP1-deficient hepatocellular carcinoma 摘要:NRF2小分子抑制剂可选择性克服keap1缺陷型肝癌患者索拉非尼耐药
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1419
Jiang Chen, Shi Jiang, Bixia Li, Tong Ji, Staiculescu Daniel, Jiayan He, Xu Junjie, Xiujun Cai
{"title":"Abstract 1419: Small molecule inhibitor of NRF2 selectively overcomes sorafenib resistance in KEAP1-deficient hepatocellular carcinoma","authors":"Jiang Chen, Shi Jiang, Bixia Li, Tong Ji, Staiculescu Daniel, Jiayan He, Xu Junjie, Xiujun Cai","doi":"10.1158/1538-7445.AM2021-1419","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1419","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81621440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract 1085: PD-L1-mediated resistance to chemotherapy is overcome by an irreversible JNK inhibitor in colorectal cancer cells 摘要:结直肠癌细胞中pd - l1介导的化疗耐药被一种不可逆的JNK抑制剂所克服
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1085
F. Sinicrope, Lei Sun, Á. Patai, Tara L. Hogenson, M. Fernandez-Zapico, B. Qin
{"title":"Abstract 1085: PD-L1-mediated resistance to chemotherapy is overcome by an irreversible JNK inhibitor in colorectal cancer cells","authors":"F. Sinicrope, Lei Sun, Á. Patai, Tara L. Hogenson, M. Fernandez-Zapico, B. Qin","doi":"10.1158/1538-7445.AM2021-1085","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1085","url":null,"abstract":"Background Colorectal cancers (CRCs) are intrinsically drug resistant tumors with frequent low or absent tumor cell PD-L1 expression. Previously, we reported that PD-L1 depletion in CRC cells can confer chemoresistance. Given that JNK signaling has been implicated in cell survival and drug resistance in CRC cells, we examined the role of JNK and its regulation in chemoresistance in CRC cells with loss of PD-L1. Materials & MethodsHuman CRC cell lines (RKO, DLD1 and HCT15) were utilized and parental and PD-L1 knockout/knockdown cells were generated. Cells were treated with a JNK1-3 inhibitor (JNK-IN-8) alone or combined with a MEK1/2 inhibitor (cobimetinib), CPT-11 or oxaliplatin. Protein/protein interaction was analyzed by immunoprecipitation (IP); protein/RNA interaction was analyzed by RNA IP assay. RNA level and half life were measured by QRT-PCR. Apoptosis was measured by cleaved caspase-3 and quantified by Annexin V labeling using FACS. Colony formation assay was performed. ResultsPD-L1 depletion in CRC cells was shown to enhance JNK activity that was due to reduced mRNA stability of the upstream CYLD deubiquitinase. Since PD-L1 competes with the ribonuclease EXOSC10 for binding to CYLD mRNA, loss of PD-L1 increases the interaction of EXOSC10 and CYLD mRNA resulting in its ribonuclease-mediated degradation and activation of JNK signaling. JNK activation increased BIM phosphorylation at Thr116 that promotes its sequestration by MCL-1 and BCL-2. Notably, a selective and irreversible JNK1-3 inhibitor (JNK-IN-8) reduces BIMThr116 phosphorylation and can release BIM from its sequestration by MCL-1 and BCL-2 to promote apoptosis. Furthermore, use of JNK-IN-8, an MCL-1 antagonist (AZD5991), or their combination in tumor cells lacking PD-L1 is shown to promote apoptosis and reduce long-term clonogenic survival induced by multiple anti-cancer drugs. As confirmation, knockdown of PD-L1 can confer drug resistance in a human colon cancer-derived organoid model that can be reversed by JNK-IN-8. Conclusion Tumor cells with low or absent PD-L1 expression show increased JNK activity that promotes BIM sequestration by MCL-1/BCL-2 to confer multiple drug resistance that can be reversed by a JNK inhibitor. Citation Format: Frank A. Sinicrope, Lei Sun, Arpad Patai, Tara L. Hogenson, Martin E. Fernandez-Zapico, Bo Qin. PD-L1-mediated resistance to chemotherapy is overcome by an irreversible JNK inhibitor in colorectal cancer cells [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 1085.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"293 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81686042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract 1328: Using whole-genome CRISPR-Cas9 screening to identify resistance networks in glioblastoma 1328:利用全基因组CRISPR-Cas9筛选鉴定胶质母细胞瘤的耐药网络
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1328
S. Budhiraja, S. Baisiwala, E. Perrault, Li Chen, Cheol Park, Chidiebere U. Awah, C. Dmello, A. Zolp, A. Sonabend, Atique U. Ahmed
{"title":"Abstract 1328: Using whole-genome CRISPR-Cas9 screening to identify resistance networks in glioblastoma","authors":"S. Budhiraja, S. Baisiwala, E. Perrault, Li Chen, Cheol Park, Chidiebere U. Awah, C. Dmello, A. Zolp, A. Sonabend, Atique U. Ahmed","doi":"10.1158/1538-7445.AM2021-1328","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1328","url":null,"abstract":"Glioblastoma (GBM) is the most aggressive and common type of adult malignant brain tumor, with 12,000 new diagnoses each year. Even with the current standard of care—surgical resection, radiation, and temozolomide (TMZ)-based chemotherapy—the median survival is about 20 months. This is partly due to the high rate of resistance to conventional therapy, including TMZ, leading to recurrence rates close to 100%. It remains largely unknown what drives the development of this resistance. Many studies have shown differences between primary and recurrent tumors, but a deeper understanding of resistance mechanisms is needed. CRISPR-Cas9 screening is a powerful tool for systematic and unbiased genetic analysis, which we applied to understand TMZ resistance. We performed a genome-wide CRISPR knockout screen in H4 human GBM cells, encompassing over 17,000 genes. A DMSO-treated population was compared with a TMZ-treated population over 14 days. In this drug sensitivity screen, depletion of guides corresponds to a TMZ-resistance gene, whereas enrichment of guides corresponds to a TMZ-sensitivity gene. Analysis showed that there was significant enrichment in guides for known TMZ-sensitivity genes that have been highly cited—ATG14, MSH6, MLH1, and PMS2—thus validating our screen results. However, more importantly, we were able to identify a list of 200 novel genes implicated in TMZ resistance. Pathway analysis revealed that these genes were enriched in Hippo and Notch signaling, both known to play a role in chemoresistance. From this list of novel genes, we identified 4 previously unstudied genes. These genes showed significant elevations in RNA expression (p Citation Format: Shreya Budhiraja, Shivani Baisiwala, Ella Perrault, Li Chen, Cheol Park, Chidiebere Awah, Crismita Dmello, Andrew Zolp, Adam Sonabend, Atique Ahmed. Using whole-genome CRISPR-Cas9 screening to identify resistance networks in glioblastoma [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 1328.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"16 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79511556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract 1289: Conjugation of indomethacin with novel oleanolic acid oximes increases its Nrf2 and NF-κB signaling pathways modulating effect in pancreatic cancer cells 摘要:吲哚美辛与新型齐墩果酸肟偶联可增强其对胰腺癌细胞中Nrf2和NF-κB信号通路的调节作用
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1289
W. Baer-Dubowska, Maria Narożna, V. Krajka-Kuźniak, B. Bednarczyk-Cwynar
{"title":"Abstract 1289: Conjugation of indomethacin with novel oleanolic acid oximes increases its Nrf2 and NF-κB signaling pathways modulating effect in pancreatic cancer cells","authors":"W. Baer-Dubowska, Maria Narożna, V. Krajka-Kuźniak, B. Bednarczyk-Cwynar","doi":"10.1158/1538-7445.AM2021-1289","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1289","url":null,"abstract":"Chronic inflammation is a key factor in the etiology of neoplastic diseases, including pancreatic cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) were approved for the chemoprevention of colon tumors and suggested for pancreas cancers prophylaxis. Anti-inflammatory and anti-tumorigenic activities are also exerted by naturally occurring and synthetic triterpenoids. Coupling of triterpenoid analogues with NSAIDs may enhance this effect and prevent the unfavorable side effects related to NSAIDs long-term use. In this study novel oleanolic acid oxime (OAO) derivatives conjugated with indomethacin (IND) differing in substitution group at position C-17 were evaluated in the context of their possible modulating effect of Nrf2-ARE and NF-κB signaling pathways in pancreatic cancer cells.PSN-1 cells were incubated for 24h with IND and OAO-IND derivatives at the concentrations of 10µM and 20µM selected based on the results of the MTT assay. The activation of Nrf2 and NF-κB was assessed by the evaluation of its translocation into the nucleus and binding to specific DNA sequences by the ELISA assay. Expression of Nrf2, SOD-1, NF-κBp50, NF-κBp65 and COX-2 was evaluated by RT-PCR and Western blot methods.Cell viability was affected mostly by 3-indomethacinoxyiminoolean-12-en-28-oic acid morpholide and 3-indomethacinoxyiminoolean-en-28-oic acid benzyl ester. The level of Nrf2 in the nucleus and binding to ARE sequence was decreased in PSN-1 cells, similarly as was NF-κBp50 and NF-κBp65 binding and nuclear accumulation. As result of diminished activation of these transcription factors decreased expression of SOD-1 and COX-2 i.e. mRNA and protein levels were found. These results indicate that the OAO-IND derivatives, particularly morpholide and benzyl ester conjugates, are more potent suppressors of NF-κB signaling pathway than IND alone. Moreover, conjugation of IND with novel OAO may protect cancer cells against chemoresistance through inhibition of the Nrf2-ARE pathway. Those novel compounds might be considered the potential modulators of hepatocellular carcinoma therapy and chemopreventive agents. Funding: This work was supported by Polish National Science Centre, grant 2016/21/B/NZ7/01758. Citation Format: Wanda Baer-Dubowska, Maria Narozna, Violetta Krajka-Kuźniak, Barbara Bednarczyk-Cwynar. Conjugation of indomethacin with novel oleanolic acid oximes increases its Nrf2 and NF-κB signaling pathways modulating effect in pancreatic cancer cells [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 1289.","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84525641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract 1479: Pan-cancer efficacy of BRAF and/or MEK inhibitors in BRAF V600-mutant multiple non-melanoma cancers: A clinico-genomic study 1479: BRAF和/或MEK抑制剂在BRAF v600突变多发性非黑色素瘤癌症中的泛癌疗效:一项临床基因组研究
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1479
J. Adashek, A. Desai, Arjun K. Menta, J. Roszik, V. Subbiah
{"title":"Abstract 1479: Pan-cancer efficacy of BRAF and/or MEK inhibitors in BRAF V600-mutant multiple non-melanoma cancers: A clinico-genomic study","authors":"J. Adashek, A. Desai, Arjun K. Menta, J. Roszik, V. Subbiah","doi":"10.1158/1538-7445.AM2021-1479","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1479","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85252796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Abstract 1137: PRMT5 inhibition regulates alternative splicing and DNA damage repair pathways in SF3B1 R625G expressing uveal melanoma cells 摘要:PRMT5抑制调控SF3B1 R625G表达葡萄膜黑色素瘤细胞的选择性剪接和DNA损伤修复途径
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1137
Koichi Ito, V. Thodima, Jack Carter, N. Bhagwat, Monisha Sivakumar, Alexander Grego, J. Rager, M. Terai, Takami Sato, O. Abdel-Wahab, Bruce R Ruggeri, P. Scherle, K. Vaddi
{"title":"Abstract 1137: PRMT5 inhibition regulates alternative splicing and DNA damage repair pathways in SF3B1 R625G expressing uveal melanoma cells","authors":"Koichi Ito, V. Thodima, Jack Carter, N. Bhagwat, Monisha Sivakumar, Alexander Grego, J. Rager, M. Terai, Takami Sato, O. Abdel-Wahab, Bruce R Ruggeri, P. Scherle, K. Vaddi","doi":"10.1158/1538-7445.AM2021-1137","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1137","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83836155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 3
Abstract 1372: Model based approach to evaluate Isatuximab (Isa) monthly dosing regimen in relapsed/refractory multiple myeloma (RRMM) 基于模型的方法评估Isatuximab (Isa)治疗复发/难治性多发性骨髓瘤(RRMM)的月给药方案
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1372
Hoai‐Thu Thai, Nadia Gaudel-Dedieu, M. Cerou, Bernard Sebastien, H. Velde, D. Semiond, C. Veyrat‐Follet
{"title":"Abstract 1372: Model based approach to evaluate Isatuximab (Isa) monthly dosing regimen in relapsed/refractory multiple myeloma (RRMM)","authors":"Hoai‐Thu Thai, Nadia Gaudel-Dedieu, M. Cerou, Bernard Sebastien, H. Velde, D. Semiond, C. Veyrat‐Follet","doi":"10.1158/1538-7445.AM2021-1372","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1372","url":null,"abstract":"Introduction: Isa is a CD38 monoclonal antibody with multiple modes of action for killing tumor cells. Isa, in combination with pomalidomide and dexamethasone (Pd), is approved for the treatment of adult pts with RRMM who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor. This study characterized the relationship between serum M-protein kinetics and progression free survival (PFS) in RRMM pts from the Phase 3 ICARIA-MM study, and simulated expected PFS outcomes when switching to a hypothetical monthly Isa dosing regimen after 6 months. Methods: A joint model of serum M-protein dynamics and PFS was developed using data from 256 pts. Pts received Isa intravenously, 10 mg/kg once weekly (QW) for 4 weeks (wks), then every other wk (Q2W) for 28-day cycles plus standard Pd (Isa-Pd) or Pd alone (control). A tumor growth inhibition model described serum M-protein kinetics under treatment effects of Isa-Pd or Pd alone; Isa exposure was predicted using individual PK parameters from the population PK analysis (Fau, PAGE Congress, 2019) and Pd exposure was predicted from K-PD model using dosing history. Trial simulations were performed using individual PK/PD parameters of ICARIA-MM pts. Results: The joint model identified instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and identified baseline pt characteristics impacting serum M-protein kinetics (serum albumin and serum β2 microglobulin on the baseline serum M-protein levels and the non-IgG type on the serum M‐protein growth rate, the serum M-protein slope) and PFS (presence of plasmacytomas). Non-IgG MM pts have similar behavior on serum M-protein kinetics for the first 60 wks even with higher exposure and similar PFS vs IgG MM pts supporting non-dose adjustment based on IgG status. Clinical trial simulation of the Isa-Pd regimen showed that switching pts on treatment at 6 months to a monthly Isa regimen would shorten the median time to progression (TTP) by 4.1 wks and median PFS by 2.3 wks (14.03 to 13.45 months). Based on TTP criteria, pts with no risk of earlier progression while switching to a monthly Isa regimen (57.7%) tend to have lower baseline tumor burden (lower serum M-protein and lower percent of bone marrow plasma cell) and better prognostic factors (higher glomerular filtration rate, higher albumin, lower β2 microglobulin). At 6 months, 85% of these pts had predicted stable ≥VGPR status. Conclusions: Trial simulations support the approved Isa 10 mg/kg QW/Q2W regimen and show that switching to a monthly Isa regimen after 6 months may reduce clinical benefit in the overall population. However, some pts with good prognosis (low tumor burden, low ISS stage, good renal function) and obtaining stable ≥VGPR status by 6 months may switch to a monthly regimen after 6 months without compromising disease progression risk; this hypothesis will be tested in a prospective clinical trial. Citation Format: Hoai-Thu Thai, Nadia Gaudel","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82272146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract 950: Targeting B7-H3 in squamous cell carcinoma of the head and neck: Preclinical proof-of-concept with the investigational anti-B7-H3 antibody-drug conjugate, MGC018 950:靶向B7-H3治疗头颈部鳞状细胞癌:抗B7-H3抗体-药物偶联物MGC018的临床前概念验证
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-950
Juniper A Scribner, Francine Z Chen, Ying Li, M. Chiechi, T. Son, J. Hooley, S. Koenig, P. Moore, E. Bonvini, C. Bohac, D. Loo
{"title":"Abstract 950: Targeting B7-H3 in squamous cell carcinoma of the head and neck: Preclinical proof-of-concept with the investigational anti-B7-H3 antibody-drug conjugate, MGC018","authors":"Juniper A Scribner, Francine Z Chen, Ying Li, M. Chiechi, T. Son, J. Hooley, S. Koenig, P. Moore, E. Bonvini, C. Bohac, D. Loo","doi":"10.1158/1538-7445.AM2021-950","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-950","url":null,"abstract":"Introduction: Squamous cell carcinoma of the head and neck (SCCHN) is the seventh most common cancer worldwide, accounting for ~ 4% of all cancers in the United States. Although PD-1-directed therapy has efficacy in SCCHN, 85-95% of patients progress following initial response. B7-H3 is a member of the B7 family of immunomodulatory molecules, is overexpressed in SCCHN, and correlates with disease severity and poor clinical outcome. Furthermore, consistent with its putative coinhibitory function, B7-H3 expression in SCCHN is inversely correlated with the number of tumor infiltrating CD8+ T-cells. We are developing therapeutics targeting B7-H3, including enoblituzumab, an Fc-engineered anti-B7-H3 monoclonal antibody, and MGC018, a duocarmycin-based B7-H3 ADC, both of which are currently being evaluated in clinical studies. Here the potential of MGC018 was explored in preclinical models as a proof of concept for targeting B7-H3 in SCCHN. Methods: Immunohistochemistry studies were performed to define the expression of B7-H3 in SCCHN tissue microarrays (TMA). Single and repeat-dose in vivo efficacy studies were conducted in CD-1 nude mice with cell line-derived SCCHN human tumor xenografts to explore the relationship between Cmax, exposure and antitumor activity, and to define the minimal efficacious dose in these models. Based on results in these cell-derived xenograft (CDX) studies, in vivo efficacy studies were extended to a panel of SCCHN patient-derived xenograft (PDX) models, which more closely mimic the biological characteristics of the patient tumor and exhibit heterogenous expression of B7-H3. Results: Analysis of B7-H3 expression on a SCCHN TMA confirmed and extended previously reported expression of B7-H3 in SCCHN. Of the SCCHN samples evaluated, 90% (36/40) of the tumor samples were positive for B7-H3: 35% (14/40) had H-scores greater than 200, with the remaining 22 samples equally distributed between the H-score range of 101-200 and 1-100 (~ 28% each). MGC018 demonstrated specific, dose-dependent in vitro cytotoxicity toward SCCHN human tumor cell lines. The in vitro cytotoxicity translated to potent antitumor activity in vivo against SCCHN CDX models, with a single administration of 3 mg/kg resulting in complete responses in 7/7 mice in the FaDu model. In the PDX setting (H-scores 120-283), repeat dose administration every week or two weeks with MGC018 at 3 mg/kg/dose, led to regressions and/or stable disease in 10/18 models, and a delay in tumor growth in 5 additional models. Conclusion: B7-H3 is frequently overexpressed in SCCHN. At clinically relevant dose levels, MGC018 demonstrated potent antitumor activity in vivo toward SCCHN CDX mouse models and the majority of SCCHN PDX mouse models examined. These results support SCCHN as a potential indication that may be responsive to ADC-based treatments directed toward B7-H3. Citation Format: Juniper A. Scribner, Francine Z. Chen, Ying Li, Michael Chiechi, Thomas Son, Jeff Hooley, Scott Koe","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82300927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abstract 1171: Assessing Melanocortin 1 receptor as a target for metastatic melanoma drug delivery 摘要:评估黑色素皮质素1受体作为转移性黑色素瘤药物递送的靶点
Experimental and Molecular Therapeutics Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-1171
Brenna M. Marks, Mengshi Li, Edwin A. Sagastume, M. Schultz, Frances L. Johnson
{"title":"Abstract 1171: Assessing Melanocortin 1 receptor as a target for metastatic melanoma drug delivery","authors":"Brenna M. Marks, Mengshi Li, Edwin A. Sagastume, M. Schultz, Frances L. Johnson","doi":"10.1158/1538-7445.AM2021-1171","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1171","url":null,"abstract":"","PeriodicalId":12258,"journal":{"name":"Experimental and Molecular Therapeutics","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82463225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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