First-in-Human, Phase I Study of PCA062 in Solid Tumors—Letter

医学 癌症研究 腺癌 癌症 内科学
作者
Bernadette de Rauglaudre,Pascal Finetti,David Jérémie Birnbaum,Marc Lopez,François Bertucci,Émilie Mamessier
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:21 (11): 1742-1743
标识
DOI:10.1158/1535-7163.mct-22-0240
摘要

In a recent issue, Duca and colleagues reported the results of a first-in-human phase I study of PCA062, an antibody–drug conjugate (ADC) targeting P-cadherin (CDH3), in patients with CDH3-positive solid tumors (1). The clinical development of PCA062 was, however, terminated due to its limited antitumor activity at MTD. Here, we would like to point out that the therapeutic development of a third-generation CDH3-ADC should still be considered as an interesting strategy for pancreatic adenocarcinoma (PAAD).PAAD is one of the most pejorative cancers with few treatment options. The most represented tumors in the Duca and colleagues’ study were esophagus and head and neck squamous cell carcinomas (respectively, ESCC n = 9, and HNSCC n = 6); the detailed information on the tumor type was not available for the other 31 patients enrolled, impeding to identify the number of patients with PAAD (at least one). Although inferior to expression in the most represented tumors in Duca and colleagues’ study, PAAD samples expressed moderate levels of CDH3, with very elevated fold-changes when compared with normal tissues (Fig. 1A). In our database (1,090 PAAD tumors), we confirmed the significant upregulation of CDH3 in primary tumors and metastases (Fig. 1B), and CDH3 overexpression was an independent poor-prognosis factor for survival (Fig. 1C). The negative Duca and colleagues’ results, notably in tumors with high CDH3 expression (ESCC, HNSCC), did not suggest that CDH3 expression could be a predictive marker for response to CDH3-ADC. A low ABCC1/SLC46A3 gene expression ratio was associated with response to this CDH3-ADC in preclinical models (2); interestingly, we found that PAAD displayed the smallest ratio when compared with 18 other carcinoma types, including HNSCC and ESCC (that displayed high and unfavorable ratios; Fig. 1D), suggesting higher potential vulnerability of PAAD.Furthermore, PAAD should also benefit from a third-generation ADC. Indeed, PCA062 is a second-generation ADC, that is, with the anti-CDH3 antibody being directly conjugated to a noncleavable maytansine-derived SMCC-DM1 linker-payload. Such ADCs were designed to kill tumors expressing high levels of target. A noncleavable linker limits the bystander killing effect of adjacent cancer cells and is less suitable in tumors with heterogeneous or moderate target expression, like CDH3 in PAAD. Finally, a DM1 payload might be less optimal than a topoisomerase-I inhibitor, as already shown in pancreatic cancer cells (3). Third-generation ADCs that associate cleavable linkers, which increase the bystander effect, and topoisomerase I inhibitors are expected to be more efficient, as exemplified by the increased efficacy of trastuzumab–deruxtecan versus Trastuzumab–DM1 in HER2+ colon and gastric cancers (4, 5).Thus, we suggest that a third-generation CDH3-ADC might be better suited in solid tumors such as PAAD and deserves further evaluation.M. Lopez is a cofounder and shareholder of Emergence Therapeutics. No disclosures were reported by the other authors.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
畅快城发布了新的文献求助10
刚刚
复成完成签到 ,获得积分10
1秒前
yinle关注了科研通微信公众号
1秒前
aktuell完成签到,获得积分10
1秒前
1秒前
ANG发布了新的文献求助10
1秒前
Lucas应助2116564采纳,获得10
1秒前
量子星尘发布了新的文献求助10
2秒前
清辉夜凝发布了新的文献求助10
2秒前
可爱的函函应助Shrine采纳,获得10
3秒前
recovery应助Aprilapple采纳,获得10
4秒前
baonali发布了新的文献求助10
5秒前
123发布了新的文献求助30
5秒前
小晓发布了新的文献求助10
5秒前
科研通AI2S应助Andema采纳,获得10
5秒前
7秒前
7秒前
10秒前
10秒前
12秒前
李健应助假发君采纳,获得10
13秒前
14秒前
KIORking发布了新的文献求助10
14秒前
落忆发布了新的文献求助10
14秒前
tengfei完成签到 ,获得积分10
14秒前
yinle发布了新的文献求助10
15秒前
15秒前
Ma发布了新的文献求助10
15秒前
15秒前
shensiang完成签到,获得积分10
16秒前
2116564发布了新的文献求助10
16秒前
17秒前
DZ完成签到,获得积分10
18秒前
俏皮小土豆完成签到,获得积分10
18秒前
Shrine发布了新的文献求助10
20秒前
炸胡娃娃完成签到,获得积分10
20秒前
清爽笑翠完成签到 ,获得积分10
20秒前
20秒前
顺利涵菡发布了新的文献求助10
22秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989444
求助须知:如何正确求助?哪些是违规求助? 3531531
关于积分的说明 11254250
捐赠科研通 3270191
什么是DOI,文献DOI怎么找? 1804901
邀请新用户注册赠送积分活动 882105
科研通“疑难数据库(出版商)”最低求助积分说明 809174