Table S3 from SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
Alexander DrilonManish R. SharmaMelissa L. JohnsonTimothy A. YapShirish M. GadgeelDale NepertGang FengMicaela B. ReddyAllison S. HarneyMohamed ElsayedAdam W. CookChristina E. WongRonald J. HinklinYutong JiangEric N. BrownNickolas A. NeitzelEllen R. LairdWen‐I WuAnurag SinghPing WeiKeith A. ChingJohn J. GaudinoPatrice A. LeeDylan P. HartleyS. Michael Rothenberg
0
Citation
0
Reference
10
Related Paper
Abstract:
<p>Supplementary Table 3: IC50 values for PF-07284892 in cell-based assays</p>Keywords:
Targeted Therapy
Table (database)
Solid tumor
<p>Supplementary Figure 4: PF-07284892 combination efficacy in additional oncogenic driver-positive mouse cancer models and monotherapy PK/PD</p>
Targeted Therapy
Solid tumor
Cite
Citations (0)
Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options. Genomic amplification and/or overexpression of the MYC oncogene is a common molecular event in HCC, thus making it an attractive target for drug therapy. Unfortunately, currently there are no direct drug therapies against MYC. As an alternative strategy, microRNAs regulated by MYC may be downstream targets for therapeutic blockade. MiR-17 family is a microRNA family transcriptionally regulated by MYC and it is commonly overexpressed in human HCCs. In this study, we performed systemic delivery of a novel lipid nanoparticle (LNP) encapsulating an anti-miR-17 oligonucleotide in a conditional transgenic mouse model of MYC driven HCC. Treatment with anti-miR-17 in vivo, but not with a control anti-miRNA, resulted in significant de-repression of direct targets of miR-17, robust apoptosis, decreased proliferation and led to delayed tumorigenesis in MYC-driven HCCs. Global gene expression profiling revealed engagement of miR-17 target genes and inhibition of key transcriptional programs of MYC, including cell cycle progression and proliferation. Hence, anti-miR-17 is an effective therapy for MYC-driven HCC.
HCCS
Targeted Therapy
Cite
Citations (38)
<p>Supplementary Figure 4: PF-07284892 combination efficacy in additional oncogenic driver-positive mouse cancer models and monotherapy PK/PD</p>
Targeted Therapy
Combination therapy
Solid tumor
Cite
Citations (0)
<p>Supplementary Figure 6: PK profiles for patients</p>
Targeted Therapy
Solid tumor
Cite
Citations (0)
<p>Supplementary Data Title Page, Methods, References</p>
Targeted Therapy
Solid tumor
Cite
Citations (0)
<p>Supplementary Figure 1: Comparison of the structures of PF-07284892, RMC445507, TNO155 bound to SHP2</p>
Targeted Therapy
Solid tumor
Cite
Citations (0)
<p>Supplementary Figure 1: Comparison of the structures of PF-07284892, RMC445507, TNO155 bound to SHP2</p>
Targeted Therapy
Solid tumor
Cite
Citations (0)
<p>Supplementary Figure 6: PK profiles for patients</p>
Targeted Therapy
Solid tumor
Cite
Citations (0)
Abstract Hepatocellular carcinoma (HCC) poses a major public health problem worldwide and novel, effective therapeutic approaches for this devastating disease are urgently needed. The overexpression or activation of the MDM2 oncogene frequently occurs in HCC and is linked to cancer growth, poor survival, metastasis, and resistance to treatment. We have hypothesized that MDM2 is a promising therapeutic target for HCC therapy. We have recently discovered that the transcription factor NFAT1 upregulates MDM2 expression, promoting cancer cell growth, migration, invasion, and angiogenesis. The present study was designed to demonstrate the role of the NFAT1-MDM2 pathway in HCC progression and its value in developing HCC targeted therapy. We systemically investigated the expression and association of MDM2 and NFAT1 in 254 pairs of human HCC and matched non-cancerous tissue samples. High-throughput virtual and cell-based screenings were carried out for search for lead compounds targeting both NFAT1 and MDM2. The in vitro and in vivo anti-HCC activities and underlying mechanisms of action were further evaluated in HCC cell lines with various p53 backgrounds. Our results demonstrated that, compared with the non-malignant peritumoral tissues MDM2 and NFAT1 were overexpressed in HCC tissues, which were correlated with poor prognosis and increased metastasis. Based on molecular modeling study, Biacore assay, and pull-down assays, one of the lead compounds, named MA242, was identified as a potent and selective MDM2 and NFAT1 dual inhibitor. Mechanistically, M242 directly bound to MDM2 and NFAT1 proteins with high affinity and induced their protein degradation. MA242 also inhibited NFAT1-mediated MDM2 transcription. At cellular level, MA242 decreased cell proliferation, and induced apoptosis and G2/M phase arrest in various HCC cell lines, regardless of the p53 status. Furthermore, M242 inhibited the tumor growth and metastasis in orthotopic and patient-derived xenograft (PDX) models of HCC, without any obvious host toxicity. In conclusion, MDM2 and NFAT1 expression can serve as predictors of survival in patients with HCC. Dual MDM2 and NFAT1 inhibitors may represent a first-in-class clinical candidates for the treatment of HCC, including tumors lacking functional p53. This project is supported by NIH R01 CA186662 and R01 CA214019 and ACS RSG-15-009-01-CDD. Citation Format: Wei Wang, Jianwen Cheng, Jiang-Jiang Qin, Bo Hu, Bhavitavya Nijampatnam, Sadanandan Velu, Xin-Rong Yang, Jia Fan, Ruiwen Zhang. Inflammation and oncogene in hepatocellular carcinoma: Clinical relevance and experimental targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3858.
Targeted Therapy
Cite
Citations (0)
<p>Supplementary Figure 2: Intermittent dosing of PF-07284892 preserves efficacy and improves tolerability preclinically</p>
Tolerability
Targeted Therapy
Cite
Citations (0)