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  • American Association for Cancer Research (AACR)  (13)
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  • American Association for Cancer Research (AACR)  (13)
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  • 1
    Online Resource
    Online Resource
    Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 15 ( 2023-08-01), p. 2791-2799
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 15 ( 2023-08-01), p. 2791-2799
    Abstract: The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC. Patients and Methods: This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR–DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. Results: Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25–0.61; P & lt; 0.0001] in Chinese patients with RAIR–DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand–foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation. Conclusions: Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-3613
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
    Online Resource
    Online Resource
    Abstract 2687: CK2 inhibitor CX-4945 modulates AKT, NF-kB, TP53 and MEK inhibitor PD-325901 targets AP1 mediated CK2 inhibitor drug resistance in head and neck cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2687-2687
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2687-2687
    Abstract: We previously identified upregulated kinase CK2 as an activator of NF-B and repressor of TP53 in promoting the malignant phenotype of head and neck squamous cell carcinoma (HNSCC). Here, we investigate the anti-tumor effects of a small molecule CK2 inhibitor CX-4945, alone and in combination with MEK inhibitor PD-0325901 (PD-901), in human HNSCC models in vitro and in vivo. CX-4945 IC50s ranged from 3.4 µM to 11.9 µM in 9 UMSCC cell lines. CX-4945 caused S and G2/M cell cycle arrest, and induced sub-G0 DNA fragments, indicating cell death. CX-4945 inhibited NF-B and BcL-XL prosurvival reporter genes in wild type (wt) TP53 (UMSCC1) and mutant (mt) TP53 (UMSCC46) cell lines, and concurrently upregulated proapoptotic TP53, p21 and prosurvival AP-1 activity only in the wtTP53 cell line. Correspondingly, CK2 phosphorylation of AKT S129 as well as T308 and S473 prosurvival signaling was reduced in both cell lines, but AP-1 inducing p-Erk1/2Thr202/204 was increased in the wtTP53 cell line. In the UMSCC1 xenografts, CX-4945 treatment significantly decreased PI3K/Akt/mTOR pathway signaling by immunostaining. While CX-4945 increased TP53 and TUNEL apoptosis marker staining at early time points (13 days after CX4945 treatment), an opposing increase in p-Erk, FosL1, cJun, JunB, and proliferation (Ki67) were also observed. Consistent with these opposing effects, no significant tumor reduction or improvement in survival was observed by CX-4945 alone. However, combination of CX-4945 with MEK/ERK inhibitor PD-901 exhibited significant synergistic anti-proliferative effects in vitro. Significant anti-tumor effects were observed with MEK inhibitor alone and in combination with CX-4945 in vivo, further supporting a role for MEK/ERK/AP-1 in resistance to CX-4945 in this HNSCC model. Supported by NIH Medical Research Scholars Program and NIDCD intramural projects ZIA-DC-000016, 73 and 74. Citation Format: Yansong Bian, Jiawei Han, Vishnu Kannabiran, Suresh Mohan, Jay Friedman, Kenna Anderes, Zhong Chen, Carter Van Waes. CK2 inhibitor CX-4945 modulates AKT, NF-kB, TP53 and MEK inhibitor PD-325901 targets AP1 mediated CK2 inhibitor drug resistance in head and neck 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 2687. doi:10.1158/1538-7445.AM2014-2687
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-2687
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 3
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    Abstract A248: Therapeutic effects of the dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor PF-04691502 on in vitro and in vivo models of head and neck squamous cell carcinoma.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. A248-A248
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. A248-A248
    Abstract: Purpose: The therapeutic potential of a novel dual inhibitor of PI3K and mTOR kinases, PF-04691502 (PF-502), was investigated in human head and neck squamous cell carcinomas (HNSCC), and a novel TGF-Receptor 1 and PTEN conditional knockout (2cKO) mouse model in which mice develop HNSCC with activation of the PI3K-mTOR pathway. Experimental Design: Human oral keratinocytes (HOK) and a panel of 9 UM-SCC cell lines were examined for activation of PI3K-mTOR signaling by Western blot. Cell proliferation was assessed by MTT assay. Human HNSCC xenografts were established utilizing 5×106 wtTP53 UM-SCC 1 and mtTP53 UM-SCC 46 cells implanted subcutaneously into the flank of SCID mice. A novel 2cKO transgenic mouse model was created by generating Tgfbr1/Pten 2cKO mice (K14-CreERtam;Tgfbr1f/f;Ptenf/f). PF-502 10 mg/kg in 0.5% methylcellulose vehicle or vehicle alone was administered by oral gavage daily for 21 days. Tumor volume, weight, and body conditioning score were measured on a M/W/F schedule. Tumor immunostaining for inhibition of PI3K-mTOR activation (pAKT, pS6) and proliferation (Ki67) was performed. Results: UM-SCC cell lines showed increased activation of the PI3K/Akt/mTOR pathway as compared with HOKs. Treatment of UM-SCC 1 and 46 with PF-502 decreased pAkt and pS6 and caused a significant decrease in cell density (IC50 1.9 uM and 0.60uM respectively). UM-SCC 1 xenograft mice treated with PF-502 showed a decreased average tumor volume of 0.96 ± 0.40 cm3 versus control, 2.49 ± 0.94 cm3 on day 21. Median survival was improved with PF-502 from 23 days to 32 days. PF-502 treatment in UM-SCC 46 xenograft mice decreased the average tumor volume of 0.36 ± 0.40 cm3 versus control at 0.55 ± 0.14 cm3 on day 21, but no survival advantage was found. In 2cKO mice, PF-502 decreased average tumor volume to 0.0036 ± 0.0005 cm3 as compared to 0.916 ± 0.060 cm3 tumor volume in control mice. HNSCC tumors in 2cKO mice on day 21 were reduced from an average of 3.23 tumors in control to 0.26 tumors in PF-502 treated mice. Median survival was also improved to 64 days with PF-502 as compared to 39 days in controls. Tumors harvested from UM-SCC 1 and 46 xenograft and 2cKO mice treated with PF-502 showed inhibition of the PI3K/Akt/mTOR pathway as evidenced by decreased pAkt and pS6, and decreased proliferation via Ki67. PF-502 caused limited or no significant weight loss or cachexia during treatment, or long term adverse effects up to 6 months after treatment. Conclusions: PI3K/mTOR pathway activation was observed in most HNSCC lines as compared with HOK cells. PF-502 inhibited the PI3K/mTOR signaling and cell density of human HNSCC cell lines in vitro. PF-502 blocked development of HNSCC in a novel 2cKO mouse model, and significantly inhibited tumor growth and improved survival in human UM-SCC 1 with wtTP53 when compared UM-SCC 46 mtTP53 xenograft tumors. PF-502 was tolerated without symptomatic weight loss at the dosage tested. These results suggest PI3K/mTOR activation is an important target for therapy in HNSCC. Supported by NIDCD project ZIA-DC-000016, NIDCR project ZIA-DE-000698, and Howard Hughes Medical Institute-NIH Scholars program (AH). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A248.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-A248
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    Online Resource
    Abstract 5052: TGF-β activates NF-κB through a TAK1-dependent and Smad7-regulated mechanism in head and neck cancer
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5052-5052
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5052-5052
    Abstract: The TGF-β signaling pathway plays a dual role in epithelial malignancies. While attenuated function of TGF-β signaling enables the development of epithelial cancers, activation of alternative TGF-β signaling in established cancer promotes a more invasive and metastatic phenotype. While the loss of its tumor suppressor function may be due to a variety of defects in the TGF-β Smad-dependent signal transduction pathway, the mechanisms responsible for the pro-oncogenic effects are less well characterized. Since aberrant activation of transcription factor Nuclear Factor-kappaB (NF-κB) promotes the malignant phenotype in head and neck squamous cell carcinomas (HNSCC), we examined whether TGF-β cross-activates NF-κB. Here, we show that TGFβ-1 treatment induced NF-κB activation and gene expression in HNSCC lines. TGFβ-1 and TNFα-induced NF-κB activation was mediated through TGF-β-activated kinase 1 (TAK1), since knocking down of TAK1 using siRNA decreased both TGFβ-1 and TNFα induced NF-κB-dependent reporter gene activity. Furthermore, TAK1 knockdown decreased degradation of IκBα, the inhibitor of NF-κB, and promoted nuclear translocation of the transactivating NF-κB subunit p65 (RELA). Consequently, p65 DNA binding activity and transcription of NF-κB downstream genes was attenuated. As TGFβ-1 treatment of HNSCC cells with mutated TGF-β Receptor II (TβRII) did not affect NF-κB-dependent reporter gene expression, functional TβRII signaling was required for activation of TAK1. Transient transfection and expression of the inhibitor SMAD7 was able to attenuate NF-κB activation as shown by NF-κB-dependent reporter gene activity, however SMAD7 preferentially decreased TGFβ-1 over TNFα induced NF-κB activation. Conversely, knocking down of SMAD7 using siRNA increased TGFβ-1 induced NF-κB activation to a greater extent than that induced by TNFα. Furthermore, TGFβ-1 treatment increased SMAD7 mRNA and overexpression of SMAD7 nearly abrogated TGF-β-induced reporter gene activity, indicating SMAD7 provides a negative feedback loop preferentially suppressing canonical TGF-β signaling. Knockdown of the NF-κB subunit p65 using siRNA decreased SMAD7 mRNA, indicating that NF-κB activation further contributes to the expression and greater inhibitory effect of SMAD7 upon TGF-β signaling. In conclusion, we show that both TGFβ-1 and TNFα can induce NF-κB activation through TAK1. Although SMAD7 was able to attenuate this TAK1/NF-κB activation, the inhibitory effect on canonical TGF-β signaling was more potent, favoring increased NF-κB-mediated cell growth and survival signaling in HNSCC. This study helps explain the dual role of TGF-β signaling, which involves activation of NF-κB and suppression of canonical TGF-β signaling in HNSCC.(Supported by NIDCD intramural project ZIADC-000016) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5052.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-5052
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 5
    Online Resource
    Online Resource
    Abstract 4324: Loss of TGF-beta receptor I and PTEN promotes HNSCC
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4324-4324
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4324-4324
    Abstract: The precise molecular mechanisms that contribute to the initiation and progression of head and neck squamous cell carcinoma (HNSCC) have not been clearly delineated. Here, we report that defects in the TGF-β and PI3K/Akt signaling pathways are common in human HNSCCs. Activation of the PI3K/Akt pathway due to PTEN deletion gives rise to hyperproliferation in the head and neck epithelia, but only a few lesions progressed to HNSCCs. Strikingly, PTEN deletion, in combination with a loss of Tgfbr1, caused HNSCC with complete penetrance. Molecular analysis revealed enhanced cell proliferation, increased expression of CCND1 and decreased expression of CDKN1A in the basal layer of the head and neck epithelia, as well as in the tumors of Tgfbr1/PTEN double conditional knockout (2cKO) mice. These tumors displayed pathology and multiple molecular alterations that resembled human HNSCCs. Furthermore, the neoplastic transformation was due to senescence evasion and was associated with an increased number of putative (CD44+, CD133+) cancer stem cells. In addition, myeloid derived suppressor cell (MDSC) infiltration, angiogenesis and immune suppression in the tumor microenvironment also accompanied mouse head and neck carcinogenesis. The Tgfbr1/PTEN 2cKO mouse model is suitable for preclinical intervention and has significant implications in the development of diagnostic cancer biomarkers as well as effective preventive and therapeutic strategies for the treatment of HNSCCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4324. doi:10.1158/1538-7445.AM2011-4324
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-4324
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 6
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    Abstract 3549: DeltaNp63 overexpression induced cytokines and chemokines attract type2 suppressive inflammatory infiltrates through NF-kappaB activation in dysplastic and malignant epithelia
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3549-3549
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3549-3549
    Abstract: We and others have previously reported that overexpression of DeltaNp63, a TP53 family member and antagonist, is often accompanied by inflammation in pre-malignant as well as cancerous lesions. However, the molecular and cellular nature of the DeltaNp63-induced inflammation and whether it favors tumorigenesis is presently unclear. Here, we report that induced expression of DeltaNp63 in the basal epidermis of transgenic (Tg) mice leads to skin erythema with a microscopically hyperproliferative epidermis and heavy infiltration of inflammatory cells. In situ phenotypic analysis of the infiltrating cells revealed increased recruitment of F4/80+ and CD11b+ macrophages, Ly6B+ neutrophils, S-100+ dentritic cells, CD45+ leukocytes, and CD3+ lymphocytes. Macrophages of the suppressive M2 phenotype were identified as a CD68+ and F4/80+/CD206+ double positive subpopulation. Transcriptome analysis of the skin lesions from DeltaNp63 Tg mice revealed 683 up-regulated genes, ∼19% of which were specifically involved in inflammation/immune responses and related signaling pathways, including many cytokine and chemokine genes. These inflammatory cytokines and chemokines inferred predominant T helper 2 and M2 signatures, and formed network connections with NF-kappaB by Ingenuity Pathway Analysis. We annotated promoter regions of these cytokine and chemokine genes by Genomatix, most of which contained predicted NF-kappaB binding consensus motifs. In addition, in human squamous cell carcinoma (SCC) lines, we showed that DeltaNp63-mediated promoter activities of chemokines and cytokines were partially blocked by knockdown of DeltaNp63, and either NF-kappaB RELA/p65 or c-REL. The reporter activities were significantly diminished when NF-kappaB sites were mutated. Supporting DeltaNp63 activation of the NF-kappaB pathway in vivo, we observed increased expression of phosphorylated NF-κB RelA/p65 (pS276), c-Rel, IKKalpha and IKKbeta in the hyperproliferative skin of DeltaNp63 Tg mice. Consistent with the aforementioned data, we observed overexpression of DeltaNp63, increased infiltrating inflammatory cells, and elevated immunohistochemistry of NF-κB signaling molecules in human SCC tissues. Together, our data support a model in which the elevated level of DeltaNp63 in the epidermis promotes NF-kappaB activation and a skewed spectrum of cytokines and chemokines, which in turn trigger type 2 suppressive inflammatory responses with characteristics of those reported in pre- and malignant squamous epithelia. Our data suggest that the most frequently mutated and aberrantly expressed TP53 family members could trigger inflammatory and immune responses, which favor tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3549. doi:1538-7445.AM2012-3549
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-3549
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 7
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    A Randomized, Phase III Study of Lenvatinib in Chinese Patients with Radioiodine-Refractory Differentiated Thyroid Cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 20 ( 2021-10-15), p. 5502-5509
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 20 ( 2021-10-15), p. 5502-5509
    Abstract: Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC. Patients and Methods: Chinese patients with confirmed RR-DTC (n = 151) were randomly assigned 2:1 to receive lenvatinib 24 mg/day or placebo in 28-day cycles. The primary endpoint was progression-free survival, and key secondary endpoints included objective response rate and safety. Analyses for progression-free survival and objective response rate were conducted using Response Evaluation Criteria in Solid Tumors v1.1 and confirmed by independent imaging review. All adverse events were assessed and monitored. Results: Progression-free survival was significantly longer with lenvatinib treatment [n = 103; median 23.9 months; 95% confidence interval (CI), 12.9–not estimable] versus placebo (n = 48; median 3.7 months; 95% CI, 1.9–5.6; hazard ratio = 0.16; 95% CI, 0.10–0.26; P & lt; 0.0001). The objective response rate was 69.9% (95% CI, 61.0–78.8) in the lenvatinib arm and 0% (95% CI, 0–0) in the placebo arm. At data cutoff, 60.2% of patients receiving lenvatinib remained on treatment; treatment-emergent adverse events led to lenvatinib discontinuation in 8.7% of patients. Overall, treatment-emergent adverse events of grade ≥3 occurred in 87.4% of patients in the lenvatinib arm, the most common being hypertension (62.1%) and proteinuria (23.3%). Conclusions: Lenvatinib at a starting dose of 24 mg/day significantly improved progression-free survival and objective response rate in Chinese patients with RR-DTC versus placebo. There were no new or unexpected toxicities. Results are consistent with those from SELECT involving patients with RR-DTC.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-0761
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
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    PI3K/mTOR Inhibitor PF-04691502 Antitumor Activity Is Enhanced with Induction of Wild-Type TP53 in Human Xenograft and Murine Knockout Models of Head and Neck Cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 14 ( 2013-07-15), p. 3808-3819
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 14 ( 2013-07-15), p. 3808-3819
    Abstract: Purpose: Phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway activation is often associated with altered expression or mutations of PIK3CA, TP53/p73, PTEN, and TGF-β receptors (TGFBR) in head and neck squamous cell carcinomas (HNSCC). However, little is known about how these alterations affect response to PI3K/mTOR–targeted agents. Experimental Design: In this preclinical study, PI3K/Akt/mTOR signaling was characterized in nine HNSCC (UM-SCC) cell lines and human oral keratinocytes. We investigated the molecular and anticancer effects of dual PI3K/mTOR inhibitor PF-04691502(PF-502) in UM-SCC expressing PIK3CA with decreased wild-type TP53, mutant TP53−/+ mutantTGFBR2, and in HNSCC of a conditional Pten/Tgfbr1 double knockout mouse model displaying PI3K/Akt/mTOR activation. Results: UM-SCC showed increased PIK3CA expression and Akt/mTOR activation, and PF-502 inhibited PI3K/mTORC1/2 targets. In human HNSCC expressing PIK3CA and decreased wtTP53 and p73, PF-502 reciprocally enhanced TP53/p73 expression and growth inhibition, which was partially reversible by p53 inhibitor pifithrin-α. Most UM-SCC with wtTP53 exhibited a lower IC50 than those with mtTP53 status. PF-502 blocked growth in G0–G1 and increased apoptotic sub-G0 DNA. PF-502 suppressed tumorigenesis and showed combinatorial activity with radiation in a wild-type TP53 UM-SCC xenograft model. PF-502 also significantly delayed HNSCC tumorigenesis and prolonged survival of Pten/Tgfbr1-deficient mice. Significant inhibition of p-Akt, p-4EBP1, p-S6, and Ki67, as well as increased p53 and TUNEL were observed in tumor specimens. Conclusions: PI3K-mTOR inhibition can enhance TP53/p73 expression and significantly inhibit tumor growth alone or when combined with radiation in HNSCC with wild-type TP53. PIK3CA, TP53/p73, PTEN, and TGF-β alterations are potential modifiers of response and merit investigation in future clinical trials with PI3K-mTOR inhibitors. Clin Cancer Res; 19(14); 3808–19. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-12-2716
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 9
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    Abstract 1058: Establishment of patient-derived organoid models of primary liver cancer and enable clinical personalized oncology
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1058-1058
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1058-1058
    Abstract: Background: Primary liver cancer (PLC) is the second cause of cancer-related mortality worldwide and includes mainly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Due to the limited treatment options and diversity of subtypes there is an unmet need to develop novel clinical approach to capture tumor heterogeneity and to guide personalized therapy in PLC. Methods: 33 surgically resected PLC patient tissues were cultured for organoid models. Patient-derived organoids (PDOs) and matched primary tumors were molecularly characterized by whole exome sequencing (WES) and RNA sequencing (RNA-seq). Subset of PDOs were screened for sensitivity to clinical medication recommended by National Comprehensive National network (NCCN) guideline to evaluate the feasibility of PLC-derived organoids in drug testing. Results:11 HCC, 1 ICC and 2 neuroendocrine tumors from patients were successfully established for organoid models. The success rate for generation of PLC organoids was 42.4% (14/33). To investigate whether organoids preserved the molecular characteristics of the originating tumors, 14 matched tumor-organoid pairs of genomic profile concordance and 3 pairs of gene expression profiles were analyzed based on WES and RNA-seq, respectively. Of the total somatic mutations found in the tumor tissues, a median of 55.5% (range 12.5% - 92.9%) mutations was observed in the corresponding PLC organoids. TP53 was the most common mutated gene either in tumors or in the organoids, with the same mutational frequency of 71.4% (10/14). Gene expression of organoids were highly correlated with their matched parental tumor tissue (median Spearman's correlation coefficient r = 0.81, range 0.76 - 0.85). To investigate the utility of PLC organoids for drug screening, multiple anti-cancer compounds (n=6-9) in standard clinical care were tested in 5 organoids which were showed high genomic concordance with their originating tumors. A good consistency between the drug screening and validation results was observed on patient NO.43 with ICC. The organoid of NO.43 was most sensitive to combined chemotherapy of irinotecan plus cisplatin. Together with drug testing result and clinical practice guidelines, this ICC patient was treated with irinotecan plus cisplatin after surgery and demonstrated durable response in clinical. In one-year follow-up no sign of recurrence was observed. Conclusion: PLC organoids intermediately to highly recapitulates the molecular and biological features of tumors. Drug sensitivity testing on PLC organoid models have the potential to guide personalized treatment in the clinical setting. Citation Format: Jianhua Rao, Feng Cheng, Long Zhang, Xiaohu Sun, Chao Song, Xuejiao Ma, Lei Ye, Wanglong Deng, Yansong Li, Zaozao Chen. Establishment of patient-derived organoid models of primary liver cancer and enable clinical personalized oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1058.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-1058
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
    Online Resource
    Online Resource
    Progressive Tumor Formation in Mice with Conditional Deletion of TGF-β Signaling in Head and Neck Epithelia Is Associated with Activation of the PI3K/Akt Pathway
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 14 ( 2009-07-15), p. 5918-5926
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 14 ( 2009-07-15), p. 5918-5926
    Abstract: The precise role of transforming growth factor (TGF)-β signaling in head and neck squamous cell carcinoma (SCC) is not yet fully understood. Here, we report generation of an inducible head- and neck-specific knockout mouse model by crossing TGF-β receptor I (Tgfbr1) floxed mice with K14-CreERtam mice. By applying tamoxifen to oral cavity of the mouse to induce Cre expression, we were able to conditionally delete Tgfbr1 in the mouse head and neck epithelia. On tumor induction with 7,12-dimethylbenz(a)anthracene (DMBA), 45% of Tgfbr1 conditional knockout (cKO) mice (n = 42) developed SCCs in the head and neck area starting from 16 weeks after treatment. However, no tumors were observed in the control littermates. A molecular analysis revealed an enhanced proliferation and loss of apoptosis in the basal layer of the head and neck epithelia of Tgfbr1 cKO mice 4 weeks after tamoxifen and DMBA treatment. The most notable finding of our study is that the phosphoinositide 3-kinase (PI3K)/Akt pathway was activated in SCCs that developed in the Tgfbr1 cKO mice on inactivation of TGF-β signaling through Smad2/3 and DMBA treatment. These observations suggest that activation of Smad-independent pathways may contribute cooperatively with inactivation of Smad-dependent pathways to promote head and neck carcinogenesis in these mice. Our results revealed the critical role of the TGF-β signaling pathway and its cross-talk with the PI3K/Akt pathway in suppressing head and neck carcinogenesis. [Cancer Res 2009;69(14):5918–26]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-4623
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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