Oral cancer is a rare cancer that occurs in the oral cavity, in areas such as the tongue, roof of mouth, floor of mouth, gum, and inside cheek. Oral cancer has frequent local recurrence and lymph node metastasis even after curative surgery with radiation to prevent recurrence. However, more than 50% of patients show a relapse pattern, and it is difficult to improve treatment due to the lack of experimental models that reflects the heterogeneity of the tumors as well as markers to predict treatment response. Although the patient-derived organoid (PDO) system is a good preclinical model that reflects the characteristics and heterogeneity of the original tumor, there are only small numbers of patients with oral cancer, so it has been relatively difficult to secure clinical samples. Therefore, oral cancer organoid development has so far been insufficient. Here, we have established a normal organoid library as well as cancer using primary tissue from many oral cancer patients. Seventy patients were enrolled in this study between Jan 2021 and Sep 2021. Fifty tumor organoids and fifty-five normal organoids were generated and sustained. Among them, 29 tumor organoids and 28 normal organoids were successfully cultured over 4 passages and cryopreserved. Moreover, 15 pairs of normal-tumor organoids were established. The success rate of organoids has no significant relationship with clinical information such as TNM stages, disease status and differentiation. These organoids recapitulated genomic features and histopathological characteristics of the patient tissue was examined through copy number variation (CNV) and IHC with TP53, P16, CK8, and so on, respectively. Normal organoids derived from tissue adjacent to the tumor of each patient showed typical morphology such as multilayer epithelium. Moreover, we set the assay system to evaluate the responses to radiation and the drug treatment using AUC value. Each organoid including normal and tumor showed different sensitivity to radiation. This oral cancer organoids platform is the largest repository in the field so far, apart from head and neck cancers. It provides a valuable platform for personalized treatment. It may also contribute to the discovery of factors associated with resistance or sensitivity to radiotherapy and chemotherapy in oral cavity cancer treatment. Citation Format: Sumin Kang, Mi Rim Lee, Sun-Young Kong, Jong-Ho Lee, Dohyun Kwon, Ikjae Kwon, Soung-Min Kim, Hye Won Shon, Yu-Sun Lee, Hyun-jin Kim, Joo Yong Park, Sung Weon Choi, Yun-Hee Kim. Development of a patient-derived organoid platform for predicting responses to standard treatments in oral cavity cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6234.
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive disease with a poor prognosis and a limited response to most of the treatments. Despite a platinum-based drug such as oxaliplatin or cisplatin is one of the most effective chemotherapy drugs for PDAC, resistance to it is a major limiting factor in PDAC treatment, indicating an urgent need for new approaches. Recently, targeting major DNA damage response (DDR) regulators such as ATM (Ataxia-telangiectasia mutated) or ATR (Ataxia telangiectasia mutated and Rad3-related) kinase has shown therapeutic potential in cancer treatment. This shows that it may be possible to enhance the responsiveness of platinum medicines via a DDR inhibition strategy. The most recently developed ATR inhibitor with the greatest potency, BAY 1895344, showed an anti-proliferative effect in clinical trials. Here, we aimed to evaluate the effect of ATR inhibition using BAY 1895344 on responsiveness to oxaliplatin in pancreatic cancer, for the first time. CFPAC-1 and Capan-2 are selected among six kinds of pancreatic cancer cell lines as oxaliplatin-sensitive and -resistant cells, respectively. According to BRAID analysis, combining the BAY 1895344 and oxaliplatin resulted in strong synergistic effects in both cell lines, particularly in Capan-2. The synergism is also confirmed in all four organoids derived from PDAC patients. We found that p-Chk1, coordinating DDR and cell cycle checkpoint, was considerably suppressed by the combined treatments, which was associated with elevated γ-H2AX intensity, cell cycle arrest and apoptosis. Moreover, we investigated the in vivo synergistic anti-tumor efficacy of combination therapy using a tumor-bearing nude mice model with CFPAC-1 and Capan-2 cells, demonstrating a substantial reduction of tumor growth in combination therapy when compared to single treatment. In conclusion, ATR inhibition enhanced the anticancer effect of oxaliplatin, and this combined therapeutic strategy may be effective in overcoming chemo-resistance in PDAC. (This study is supported by National Cancer Center, Republic of Korea (No. 2212470, 2010330)) Citation Format: Hye Won Shon, Jung Won Chun, Jeong Eun Gong, Mi Rim Lee, Yu-Sun Lee, Sumin Kang, Sunshin Kim, Sang Myung Woo, In Rae Cho, Woo Hyun Paik, Woo Jin Lee, Ji Kon Ryu, Yong-Tae Kim, Sang Hyub Lee, Yun-Hee Kim. Inhibiting ataxia-telangiectasia mutated and RAD3-related (ATR) by BAY 1895344 overcomes chemoresistance to oxaliplatin and promotes synergistic anti-tumor effect in pancreatic cancer [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 6217.
Oral cancer is rare cancer that accounts for roughly 1.5% of all cancers in Korea. The standard treatment for the patient with oral cancer is surgery followed by radiotherapy. However, 30-50% of patients had local recurrence and metastasis to lymph nodes within 2 years. Numerous radiation-resistant cell lines have been created and utilized for research due to the significance of biomarkers for predicting response to radiation therapy; however, the homogenous 2D cell lines limit the practical use of the identified molecules. Patient-derived organoid (PDO) systems, as opposed to 2D cell lines, have significant advantages for the preclinical model in that they are similar to the genetic heterogeneity seen in patient tumors and reflect the clinical characteristics of patients. In this study, we generated organoid models that mimic radiation therapy from the oral PDO library in order to identify molecular profiles associated with radiation resistance. From January 2021 to August 2022, we prospectively collected 164 normal tissues and 179 tumor tissues from enrolled patients with oral cancer. 60 tumor organoids and 66 normal organoids were maintained over 4 passages and cryopreserved, which is the largest PDO repository with normal and malignant ever published for oral cancer to date. Each organoid was identified through long-term clinical information follow-up in their respective patients, notably recurrence after radiation therapy. In the oral PDO library, organoids were categorized as derived from tumor tissues of non-recurred patients (nPDOs), derived from primary tumor tissues of patients who recurred after radiotherapy (pPDOs), and derived from recurrent tumor tissues (rPDOs). There was also one pair of pPDO and rPDO for the same patient. A total of 60 Gy of radiation was irradiated to the organoids for the construction of a radiation-resistant PDO model, and finally, four cases of radiotherapy mimic organoid models were successfully established. Survival analysis for radiation dose-response and post-irradiation calcein-AM staining were used to validate these models. The pPDO and rPDO models of radiation resistance are well-established, whereas nPDO was not. Given the rarity of oral cancer, this platform is the first preclinical model to closely resemble the clinical radiation pipeline for patients with oral cancer. It would help make a more accurate prediction of radiation response in patients with oral cancer, as well as the development of treatment guidelines. (This research was supported by National Cancer Center, Korea (No. 2210980) and National Research Foundation of Korea (NRF) grant, funded by the Korean government (MSIT) (No. 2020M3A9A5036362)) Citation Format: Sumin Kang, Mi Rim Lee, Sun-Young Kong, Jong-Ho Lee, Dohyun Kwon, Ikjae Kwon, Soung-Min Kim, Youngwook Kim, Wonyoung Choi, Hye Won Shon, Yu-Sun Lee, Joo Yong Park, Sung Weon Choi, Yun-Hee Kim. Patient-derived organoid platform for the prediction of radiation response and modeling radiation resistance in oral cancer [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 2404.
Purpose Cancer is one of the leading causes of death worldwide. Patient-derived tumor cells can serve as a powerful resource for studying pathophysiologic mechanisms and developing robust strategies for precision medicine. To address this problem, we launched the patient-derived organoids (PDOs) Hub to establish a comprehensive model of various tumor organoids from pancreatic, biliary tract, liver, colorectal, breast, gastric, ovarian, and oral cancers, with matching clinical data and molecular characteristics. Methods All specimens were collected from histologically confirmed cancer patients at the National Cancer Center. Samples obtained from surgery, biopsy, or body fluid (malignant ascites or pleural effusion) were collected for ex vivo culture of tumor cells. PDOs were managed according to our standard operating procedure (SOP), which included specimen delivery process, separation of cells from tissues, criteria for subculture, quality control (QC), production of genomic and histologic data, and the 384-well-based drug response evaluation system. Organoids were considered to be successfully cultured when they were maintained for five or more passages. Results A total of 263 PDOs were established from various cancer types, including oral cancer (N = 89), pancreatic cancer (N = 48), ovarian cancer (N = 32), breast cancer (N = 30), biliary tract cancer (N = 29), hepatocellular carcinoma (N = 17), gallbladder cancer (N = 8), gastric cancer (N = 7) and colorectal cancer (N = 3). PDOs broadly recapitulated the histologic and genetic characteristics of the patient’s tumor. These organoids available for long-term culture were cryopreserved, and a total of 2986 stocks have been accumulated. Drug screening tests were performed with 60 PDOs (pancreatic cancer, N = 36; breast cancer, N = 15; ovarian cancer, N = 6; gastric cancer, N = 3) using selected agents among the 47 drugs for each type of cancer. Profiles of cytotoxic agents were well correlated with the patient’s clinical responses to the matched drugs and tested investigational agents also showed promising antitumor activity. Conclusions We have established a model of several human cancer organoids. This will serve as the platform that can recapitulate the physiology and drug response profiles of human cancer and pave the way for screening innovative drugs, identifying novel targets, and stratifying patients for pertinent therapeutic options. (This work was supported by National Research Foundation of Korea grant, funded by the Korean government (MSIT) (No. 2020M3A9A5036362)) Citation Format: Yebeen Yu, Mi Rim Lee, Wonyoung Choi, Sumin Kang, Jeong Eun Gong, Soobeen Heo, Hye Ju Park, Sang Myung Woo, So-Youn Jung, Sung Weon Choi, Jong-Ho Lee, Myong Cheol Lim, Ji Yeon Baek, Bo Hyun Kim, Ji Hoon Kim, Yuri Cho, Sang-Jae Park, Yun-Hee Kim, Sun-Young Kong. Patient-derived organoids (PDOs) hub of National Cancer Center, Korea: pre-clinical model for drug screening [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 161.
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