Prospective experimental treatment of colorectal cancer patients based on organoid drug responses

Abstract

Background: Organoid technology has recently emerged as a powerful tool to assess drug sensitivity of individual patient tumors in vitro. Organoids may therefore represent a new avenue for precision medicine, as this circumvents many of the complexities associated with DNA-or transcriptional-profiling. Materials and methods: The SENSOR trial was a single-arm, single-center, prospective intervention trial to evaluate the feasibility of patient-derived organoids to allocate patients for treatment with off-label or investigational agents. The primary endpoint was an objective response rate of !20%. Patients underwent a biopsy for culture before commencing their last round standard of care. Organoids were exposed to a panel of eight drugs and patients were treated after progression on standard-of-care treatment and when a clear signal of antitumor activity was identified in vitro.Results: Sixty-one patients were included and we generated 31 organoids of 54 eligible patients. Twenty-five cultures were subjected to drug screening and 19 organoids exhibited substantial responses to one or more drugs. Three patients underwent treatment with vistusertib and three with capivasertib. Despite drug sensitivity of organoids, patients did not demonstrate objective clinical responses to the recommended treatment. Conclusions: Organoid technology had limited value as a tool for precision medicine in this patient population because a large fraction of patients could not undergo treatment or because the recommended treatment did not elicit an objective response. We identified several essential parameters, such as the culture success rate, clinical deterioration of patients during standard of care, and rational design of drug panels that need to be accounted for in organoid-guided clinical studies.

Organoids and Colorectal Cancer

“…The first formal, prospective intervention trial, the Selecting Cancer Patients for Treatment Using Tumor Organoids (SENSOR) trial, was designated to evaluate the potential and feasibility of using PDTOs to guide experimental treatment decision in metastatic CRC patients without curative treatment options. The results have not demonstrated concordance between drug sensitivity of organoids and patient clinical responses [ 130 ]. As said by the authors, putative reasons for this include the low culture success rate (due to the small size and low quality/small amount of tumor cell content of biopsies), clinical deterioration of patients during standard of care and the insufficient rational design of drug panels.…”

Patient-Derived Explants of Colorectal Cancer: Histopathological and Molecular Analysis of Long-Term Cultures

“…In comparison to state-of-the-art methods, such as patient-derived organoids, in PDE we were able to retain both tumour cells and features of TME that cannot be captured in epithelial-restricted organoids [ 61 ]. Recently, metastatic CRC patients that received organoid-guided treatment choice did not show clinical benefit [ 62 ], highlighting the need for additional studies on their therapeutic predictability. Although limited by initial sample size, CRC-PDE require a small amount of original tumour to achieve multiple explants per sample.…”

Organoid Models for Cancer Research—From Bed to Bench Side and Back

“…Up to now, most studies have been observational in nature. Only a small number of studies, such as that of Narasimhan et al or the recently published one of Ooft et al, are of interventional design [ 97 , 98 ]. Ooft et al performed a single-arm, single-center, prospective intervention trial to address whether optimal therapy for a patient can be chosen according to his/her organoids´ response in a drug screening assay [ 98 ].…”

“…Only a small number of studies, such as that of Narasimhan et al or the recently published one of Ooft et al, are of interventional design [ 97 , 98 ]. Ooft et al performed a single-arm, single-center, prospective intervention trial to address whether optimal therapy for a patient can be chosen according to his/her organoids´ response in a drug screening assay [ 98 ]. This study was conducted on patients with metastatic, incurable CRC who passed first and second line chemotherapy but did not enter in last line/experimental therapy.…”

“…The tested agents comprised five FDA approved drugs and three drugs in an advanced phase of development (vistusertib, capivasertib, selumetinib, gefitinib, palbociclib, axitinib, gedatolisib and glasdegib). A drug screening was performed for 25 of the 61 initial patients; 19 patients were eligible to obtain study treatment and finally six patients received the allocated study medication based on a therapeutic screening of their organoids [ 98 ]. There was no significant and durable clinical response upon treatment with organoid-identified medication [ 98 ].…”