Patient-derived Organoid Model for Predicting the Chemoresponse in Patients With Colorectal Cancer.

Cancer mortality has decreased due to the contribution of extensive research on cancer treatment, including chemotherapy, radiation, and immunotherapy. However, histopathologically similar tumors originating from the same organ are treated with identical or similar chemotherapeutic regimens regardless of patient characteristics or cancer subtypes. The aim of this study was to evaluate the utility of organoids in predicting responses to chemotherapeutic agents. This study retrospectively reviewed patient-derived organoids (PDOs) from 10 colorectal cancer patients to compare chemotherapy responses. Drug sensitivities for 5-fluorouracil (5-FU), cisplatin, oxaliplatin, and irinotecan were compared using GI50 (concentration that inhibits cancer cell growth by 50%). When organoids were treated with 5-FU, GI50 was the lowest compared to the other three chemotherapeutic agents (cisplatin, oxaliplatin, and irinotecan). The responsiveness to chemotherapeutic agents differed depending on specific patient characteristics including age, tumor location, stage, and gross type. The response of the patients' organoids to chemotherapeutic agents was consistent with the response to chemotherapy actually performed in those patients with cancer recurrence after surgery. PDOs may be useful as a preclinical model in predicting chemotherapy responses in cancer patients.

Yi K ，Park SH ，Kim DU ，Jeon DY ，Lee HJ ，Song GA ，Jo HJ ，Baek DH ，Han JH ，Lee BC ... -  《-》

Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response.

The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies. We optimized drug screen methods on 5-11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness. Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003). Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens.

Smabers LP ，Wensink E ，Verissimo CS ，Koedoot E ，Pitsa KC ，Huismans MA ，Higuera Barón C ，Doorn M ，Valkenburg-van Iersel LB ，Cirkel GA ，Brousali A ，Overmeer R ，Koopman M ，Braat MN ，Penning de Vries B ，Elias SG ，Vries RG ，Kranenburg O ，Boj SF ，Roodhart JM ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Patient-Derived Organoid Model in the Prediction of Chemotherapeutic Drug Response in Colorectal Cancer.

Hao M ，Cao Z ，Wang Z ，Xin J ，Kong B ，Xu J ，Zhang L ，Chen P ... -  《ACS Biomaterials Science & Engineering》

Modulators of the Nrf2 Signaling Pathway Enhance the Cytotoxic Effect of Standard Chemotherapeutic Drugs on Organoids of Metastatic Colorectal Cancer.

The activity of known modulators of the Nrf2 signaling pathway (bardoxolone and brusatol) was studied on cultures of tumor organoids of metastatic colorectal cancer previously obtained from three patients. The effect of modulators was studied both as monotherapy and in combination with standard chemotherapy drugs used to treat colorectal cancer. The Nrf2 inhibitor brusatol and the Nrf2 activator bardoxolone have antitumor activity. Moreover, bardoxolone and brusatol also significantly enhance the effect of the chemotherapy drugs 5-fluorouracil, oxaliplatin, and irinotecan metabolite SN-38. Thus, bardoxolone and brusatol can be considered promising candidates for further preclinical and clinical studies in the treatment of colorectal cancer.

Razumovskaya AV ，Silkina MO ，Nikulin SV ，Tonevitsky AG ，Alekseev BY ... -  《-》

Organoids Derived from Neoadjuvant FOLFIRINOX Patients Recapitulate Therapy Resistance in Pancreatic Ductal Adenocarcinoma.

We investigated whether organoids can be generated from resected tumors of patients who received eight cycles of neoadjuvant FOLFIRINOX chemotherapy before surgery, and evaluated the sensitivity/resistance of these surviving cancer cells to cancer therapy. We generated a library of 10 pancreatic ductal adenocarcinoma (PDAC) organoid lines: five each from treatment-naïve and FOLFIRINOX-treated patients. We first assessed the histologic, genetic, and transcriptional characteristics of the organoids and their matched primary PDAC tissue. Next, the organoids' response to treatment with single agents-5-FU, irinotecan, and oxaliplatin-of the FOLFIRINOX regimen as well as combined regimen was evaluated. Finally, global mRNA-seq analyses were performed to identify FOLFIRINOX resistance pathways. All 10 patient-derived PDAC organoids recapitulate histologic, genetic, and transcriptional characteristics of their primary tumor tissue. Neoadjuvant FOLFIRINOX-treated organoids display resistance to FOLFIRINOX (5/5), irinotecan (5/5), and oxaliplatin (4/5) when compared with treatment-naïve organoids (FOLFIRINOX: 1/5, irinotecan: 2/5, oxaliplatin: 0/5). 5-Fluorouracil treatment responses between naïve and treated organoids were similar. Comparative global transcriptome analysis of treatment-naïve and FOLFIRINOX samples-in both organoids and corresponding matched tumor tissues-uncovered modulated pathways mainly involved in genomic instability, energy metabolism, and innate immune system. Resistance development in neoadjuvant FOLFIRINOX organoids, recapitulating their primary tumor resistance, suggests continuation of FOLFIRINOX therapy as an adjuvant treatment may not be advantageous for these patients. Gene-expression profiles of PDAC organoids identify targetable pathways involved in chemoresistance development upon neoadjuvant FOLFIRINOX treatment, thus opening up combination therapy possibilities.

Farshadi EA ，Chang J ，Sampadi B ，Doukas M ，Van 't Land F ，van der Sijde F ，Vietsch EE ，Pothof J ，Koerkamp BG ，van Eijck CHJ ... -  《-》