Drug For Squamous Cell Carcinoma Research Articles

Nation-wide survey of advanced non-melanoma skin cancers treated at dermatology departments in Japan

BackgroundThere are limited treatment options for advanced non-melanoma skin cancers (NMSCs). To overcome this issue, we need to conduct clinical studies, however, there is a lack of information on how many patients with advanced NMSCs are treated annually in Japan. ObjectiveTo investigate the actual number of advanced NMSC patients in Japan. MethodsA questionnaire survey was sent to 668 institutes to educe information on: 1) the numbers of patients with squamous cell carcinoma (SCC), extramammary Paget disease (EMPD), other skin origin carcinomas, and cutaneous angiosarcoma (CAS) admitted in 2016 and 2017; 2) the preferred first- and second-line chemotherapies; and 3) the anticipated for future development. ResultsQuestionnaires were returned from 383 (57.3%) institutes. They reported a total of 1765 patients over the 2 years. The annual number patients with SCC, EMPD, other skin carcinomas, and CAS was 323.5, 192.5, 126, and 240.5, respectively. We estimated the annual number of patients for all 668 institutes to be 1255.6. Current first- and second-line treatment for NMSCs were chemotherapy regimens, but immune checkpoint inhibitors were the most anticipated new drugs for SCC and CAS, while chemotherapy was still the most anticipated treatment for EMPD. ConclusionConsidering that during 2017, the number of deaths in Japan due to NMSC was reported to be 948, our estimated annual number of patients with NMSCs, 1255.6 seems to be an accurate estimation. As most of the treatment options for advanced NMSCs are outdated, the results of this study should be used to propose clinical studies.

Abstract 1228: Nintedanib selectively inhibits the activation and tumor-promoting effects of fibroblasts from lung adenocarcinoma patients

Abstract Nintedanib (BIBF 1120) is a multikinase inhibitor recently approved to treat lung adenocarcinoma (ADC) patients based on the therapeutic benefits reported in clinical trials on ADC but not on squamous cell carcinoma (SCC), which are the two most common lung cancer subtypes. However, the biological processes underlying the selective anticancer function of nintedanib in ADC remain obscure. To shed light on this gap of knowledge, we examined the role of tumor-associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in vivo, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with TGF-β1, which is a potent fibroblast activator frequently upregulated in lung cancer. Nintedanib dose-dependently inhibited the TGF-β1-induced expression of activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved parenchyma, whereas such inhibiton was very modest in SCC-TAFs, thereby suggesting that TAF activation is regulated by different mechanisms in ADC and SCC. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC. These results reveal that nintedanib is a potent inhibitor of fibrosis and its associated tumor-promoting effects in ADC, and strongly suggest that the subnormal antifibrotic response of SCC-TAFs to nintedanib may underlie the lack of therapeutic benefits of this drug in SCC. Our findings also support that preclinical models based on carcinoma-TAF interactions may help unraveling the resistance mechanisms of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug. Citation Format: Jordi Alcaraz, Marta Gabasa, Rafael Ikemori, Noemí Reguart. Nintedanib selectively inhibits the activation and tumor-promoting effects of fibroblasts from lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1228. doi:10.1158/1538-7445.AM2017-1228

Low-dose hyperthermia enhances the antitumor effects of chemotherapy in squamous cell carcinoma.

Esophageal squamous cell carcinoma is a highly aggressive neoplasm and the sixth leading cause of global cancer-related death; the 5-year survival rate for esophageal cancer is only about 20%-25% for all stages. Therefore, improving the therapeutic effect is important. This study assessed whether low-dose hyperthermia (LDH) enhances the antitumor effects of chemotherapy. The antitumor effect of chemotherapy with/without LDH in the squamous cell carcinoma cell line SCCVII was evaluated. A comprehensive analysis was performed with real-time polymerase chain reaction (PCR) to study the hyperthermia-induced changes in the gene expression of SCCVII cell lines. In addition, the cytotoxic and apoptotic changes in the cells treated with LDH combined with/without 5-fluorouracil (5-FU) were measured. LDH combined with 5-FU (10 nM) strongly inhibited the cell growth of SCCVII, with flow cytometry showing an increased population of apoptotic cells. PCR showed that LDH promoted a 25.22-fold increase of p53 mRNA and 18.08-fold increase of Bax mRNA in vitro. MDR1 expression was decreased to 28.7% after LDH. This treatment can result in much higher efficacy of antitumor drugs. After LDH, the expressions of TS decreased to 12.06%, OPRT increased by 4.17-fold, and DPD did not change (1.03-fold). This transformations will induce susceptibility to 5-FU. LDH may be a useful enhancer of chemotherapy drugs for squamous cell carcinoma.

Abstract 825: Id3: Tumor suppressor of squamous cell carcinoma.

Abstract Skin cancer, the most common type of cancer with more than 1 million cases diagnosed in the US every year, occurs at least once to about half of Americans 65 years or older. The three main types of skin cancer—Basal Cell Carcinoma (BCC), Squamous Cell Carcinoma (SCC), and melanoma have mortality rates that are estimated to be 0.1%, 4.3% and 10% respectively in 2011. The Inhibitor of DNA Binding/Differentiation 3 (Id3) protein, a helix-loop-helix (HLH), dominant negative transcription factor, is one of four Id proteins found in mammals (Id1-4). The Id protein family plays a role in many cellular processes, including differentiation, proliferation, apoptosis, and angiogenesis. Previous studies in the Rosenthal lab have shown that Id3 over-expression in immortalized human keratinocytes induces apoptosis in part by activation of a Bax-caspase-9-caspase-3-dependent mitochondrial pathway via upregulation of bax promoter activity. To further elucidate the roles of Id3 in apoptosis, proliferation, and tumorigenesis, our studies focused on effects of induced Id3 expression on tumor growth in vivo. To investigate the role of Id3 in SCC, a tetracycline (Tet)-regulated expression (T-REx™) system was utilized to induce Id3 expression in A431 cells, a human malignant cervical SCC cell line. Immunoblot and RT-PCR analysis of A431-TRex-Id3 cells verified Id3 expression in the presence of Tet. When Id3 was induced by Tet in these cells in vitro, caspase-3 and -9 were activated. Cells were stably transfected with GFP to monitor tumor growth over thirty days by Maestro® in vivo imaging. Effects of Id3 on tumorigenesis in vivo was examined by subcutaneous injection of these cells onto athymic nude mice, half of which were fed with a doxycycline (Dox; a tetracycline derivative)-containing feed, leading to induced Id3 expression in the tumor, and half with a regular diet. Subcutaneously-injected A431 cells formed significantly (50%) smaller tumors upon Id3 induction. Immunofluorescent staining of tumor sections from Dox-fed mice revealed a 1.5-fold increase in active caspase-3 but no significant change in Ki-67, a proliferation marker. To investigate the mechanism of tumor shrinkage caused by Id3, microarray analysis was performed, and four genes were found to be significantly up- or down-regulated by Id3. Id3 deletion mutants were further created to study the domain(s) responsible for the decrease in tumor size. Mutation analysis showed that Id3 induces Max dimerization protein 3 (MXD3) protein expression through its HLH domain. Other candidate genes remain to be tested. The role of Id3 in SCC cell killing by cisplatin, a commonly used chemotherapeutic drug for SCC, is also currently under investigation. Our results together indicate that Id3 is a potential apoptosis inducer and therefore a therapeutic target in treating SCC. Citation Format: You-Shin Chen, Cynthia Rosenthal, Dean Rosenthal. Id3: Tumor suppressor of squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 825. doi:10.1158/1538-7445.AM2013-825

The effect of coptis chinensis on the signaling network in the squamous carcinoma cells

The effects of Coptis chinensis on the behavior of squamous cell carcinoma have not yet been established. We examined the anticancer activity of Coptis chinensis on human squamous carcinoma cells, both in vitro and in xenografted nude mice, and applied Pathway Array Technology to understand possible involvement of signaling pathways in Coptis Chinensis induced tumor cells inhibition as well. Following Coptis chinensis treatment, a time-dependent reduction in proliferation was observed in both cell lines and NCR/NU mice. Coptis chinensis has a wide effect on cell signaling, including cell cycle regulation (Cdk6, Cdk4, cyclin B1, cyclin E, cyclin D1, p27), cell adhesion (E-cadherin, osteopontin), differentiation, apoptosis(p-Stat3, p53, BRCA1), cytoskeleton (p-PKC α/β II, Vimentin, p-PKCα), MAPK signaling (raf-1, ERK1/2, p-p38, p-ERK), and the phosphatidylinositol 3-kinase signaling pathway (p-Akt, Akt, p-PTEN). In our conclusions, Coptis chinensis may be a novel therapeutic drug for squamous cell carcinoma.

Investigator-initiated Investigational New Drug (IND) Trial of S-1 for Esophageal Cancer and Recent Progress on Molecular Targeted Drugs for Squamous Cell Carcinoma of the Esophagus and Head and Neck

Investigator-initiated Investigational New Drug (IND) Trial of S-1 for Esophageal Cancer and Recent Progress on Molecular Targeted Drugs for Squamous Cell Carcinoma of the Esophagus and Head and Neck

Court denies constitutional right to experimental drugs

A legal battle to force FDA to allow terminally ill patients early access to experimental drugs outside of clinical trials was recently decided in the agency’s favor, but the fight may not be over yet. Judges on the U.S. Court of Appeals for the District of Columbia Circuit on August 7 ruled 8 to 2 that dying patients have no fundamental constitutional right to experimental therapy, reversing an earlier decision by a three-judge panel of the court. The lawsuit and appeal, by the Washington Legal Foundation (WLF) on behalf of the Abigail Alliance for Better Access to Developmental Drugs, were filed against FDA and the Department of Health and Human Services in 2003. The Abigail Alliance is named after Abigail Burroughs, a young woman who sought treatment with investigational drugs for squamous cell carcinoma but died of the disease in 2001 without gaining access to the drugs, both of which have since been approved for the U.S. market.