Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.
Histone lysine methyltransferase NSD2 (WHSC1/MMSET) is overexpressed frequently in multiple myeloma due to the t(4;14) translocation associated with 15% to 20% of cases of this disease. NSD2 has been found to be involved in myelomagenesis, suggesting it may offer a novel therapeutic target. Here we show that NSD2 methyltransferase activity is crucial for clonogenicity, adherence, and proliferation of multiple myeloma cells on bone marrow stroma in vitro and that NSD2 is required for tumorigenesis of t(4;14)þ but not t(4;14)À multiple myeloma cells in vivo. The PHD domains in NSD2 were important for its cellular activity and biological function through recruiting NSD2 to its oncogenic target genes and driving their transcriptional activation. By strengthening its disease linkage and deepening insights into its mechanism of action, this study provides a strategy to therapeutically target NSD2 in multiple myeloma patients with a t(4;14) translocation. Cancer Res; 73(20); 6277-88. Ó2013 AACR.
Background: Esophageal cancer is the eighth most common cancer and the sixth most common cause of cancer related death in the world. Squamous cell carcinoma is the predominant histologic subtype of esophageal cancer, particularly in Asia. Currently, no targeted therapy has been approved for treating this type of disease. Platinum-based combination chemotherapy remains to be the standard care for first line treatment of advanced or metastatic esophageal cancer with limited efficacy. Activation of EGFR/HER3/PI3K pathway is frequently observed in esophageal cancer, however, their therapeutic value remains to be further tested.
Methods: In this study, we evaluated the anti-tumor activity of LJM716, a fully human anti-HER3 antibody, either alone or in combination with anti-EGFR antibody cetuximab or PI3K alpha subunit inhibitor BYL719 in esophageal squamous cancer. LJM716, cetuximab and BYL719 single agent as well as their pair-wised combination activity were assessed in 24 esophageal squamous cancer cell (ESCC) lines using the CellTiter-Glo® Luminescent Cell Viability Assay. Single agent and combination anti-tumor activities of these reagents were also tested in selected cell line xenograft and patient derived xenograft mouse models.
Results: NRG1 expression (60%), PIK3CA mutation (8%), moderate PIK3CA (30%) and EGFR (30%) amplification were detected in a panel of 24 ESCC lines. Anti-HER3 antibody LJM716 potently inhibited HER3 phosphorylation and decreased pAKT level in these cell lines. In vitro, LJM716 inhibited proliferation of a sub-set of ESCC lines. LJM716 further enhanced and broadened the anti-tumor activities of both BYL719 and cetuximab in ESCC lines. In mouse xenograft models, LJM716 single agent treatment induced tumor stasis while combination with either BYL719 or cetuximab induced model dependent tumor regression.
Conclusion: NRG1-HER3-PI3K pathway activation is commonly observed in esophageal squamous cell cancer. Activation of HER3 is a potential mechanism leading to resistance to EGFR or PI3K targeted therapies, and combining anti-HER3 therapies with therapies targeting PI3K/EGFR may provide new therapeutic strategy for patients with esophageal squamous cell cancer.
Citation Format: Qing Sheng, Hui-Qin Wang, rita das, yan chen, jinsheng liang, Fiona Xu, zongyao Wang, Z. Alexander Cao, youzhen Wang, alan huang. ljm716, an anti her3 antibody that inhibits her3 dimerization, displays anti-tumor activity in esophageal squamous cell cancer. [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 2612. doi:10.1158/1538-7445.AM2014-2612
<p>PDF file, 989K, Depletion of NSD2 has only mild effects on myeloma cell proliferation. Supplementary Figure S2. NSD2 is important for tumorigenesis of t(4;14)+ myeloma cells. Supplementary Figure S3. PHD domains are important for cellular H3K36me2 activity of NSD2 but not in vitro enzymatic activity. Supplementary Figure S4. NSD2 activity mediates transcription activation of t(4;14)+ specific myeloma gene set. Supplementary Figure S5. NSD2 overexpression driven by t(4;14) translocation abolished global association of H3K36me2 with gene transcription. Supplementary Figure S6. NSD2 overexpression driven by t(4;14) translocation abolished positive correlation of H3K36me2 with gene transcription.</p>
<p>XLSX file, 863K, Lists of differentially expressed genes (DEGs) from comparisons of PAR_TKO and active_inactive groups and overlapping DEGs (p<0.05).</p>
<p>XLSX file, 863K, Lists of differentially expressed genes (DEGs) from comparisons of PAR_TKO and active_inactive groups and overlapping DEGs (p<0.05).</p>
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