Tumor organoids are 3D cultures of cancer cells. They can be derived from the tumor of each individual patient, thereby providing an attractive ex vivo assay to tailor treatment. Using ...patient-derived tumor organoids for this purpose requires that organoids derived from biopsies maintain the genetic diversity of the in vivo tumor. In this study tumor biopsies were obtained from 14 patients with metastatic colorectal cancer (i) to test the feasibility of organoid culture from metastatic biopsy specimens and (ii) to compare the genetic diversity of patient-derived tumor organoids and the original tumor biopsy. Genetic analysis was performed using SOLiD sequencing for 1,977 cancer-relevant genes. Copy number profiles were generated from sequencing data using CopywriteR. Here we demonstrate that organoid cultures can be established from tumor biopsies of patients with metastatic colorectal cancer with a success rate of 71%. Genetic analysis showed that organoids reflect the metastasis from which they were derived. Ninety percent of somatic mutations were shared between organoids and biopsies from the same patient, and the DNA copy number profiles of organoids and the corresponding original tumor show a correlation of 0.89. Most importantly, none of the mutations that were found exclusively in either the tumor or organoid culture are in driver genes or genes amenable for drug targeting. These findings support further exploration of patient-derived organoids as an ex vivo platform to personalize anticancer treatment.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual ...patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer. Furthermore, we demonstrate that these T cells can be used to assess the efficiency of killing of matched tumor organoids. This platform provides an unbiased strategy for the isolation of tumor-reactive T cells and provides a means by which to assess the sensitivity of tumor cells to T cell-mediated attack at the level of the individual patient.
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•Induction of tumor-reactive T cells by co-culture of PBMCs and tumor organoids•Induced T cell populations do not recognize healthy organoids or tissue•This platform can be used to assess the efficiency of T-cell-mediated tumor killing
A modified patient-derived tumor organoids system allows the expansion of tumor-specific T cells from blood for personalized analysis of their anti-cancer properties.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mesenchymal stem cells (MSCs) can play a vital role in tumor progression and anticancer therapy response, as demonstrated by various in vitro and in vivo model systems. Their ability to home to ...developing tumors and modulate the tumor microenvironment, by suppressing T‐cell responses and contributing to the tumor stroma, is suggested to have a significant impact on disease progression, metastasis formation, and therapy response. Most evidence, however, is derived from artificial models using exogenously administered MSCs. The contribution of endogenous MSCs to tumor progression is currently unclear. Furthermore, few studies have been conducted in humans. A prospective biomarker study was therefore undertaken in 40 human cancer patients and 10 healthy controls of similar age, aimed at (i) exploring and quantifying circulating MSC levels in healthy volunteers and patients with advanced malignancies, (ii) determining the variability of MSC levels between healthy volunteers and cancer patients with different histologic tumor types, and (iii) exploring biomarkers associated with MSC levels. Significantly increased levels of circulating MSC‐like cells were observed in cancer patients when compared to healthy individuals (1.72 fold difference, 95% CI 1.03–2.81%, p = 0.03). In addition, prior systemic therapy was associated with a significant increase in MSC‐like cells (1.73 fold difference, 95% CI 1.02–2.95, p = 0.04). These results indicate that the amount of endogenously circulating MSCs in humans is increased in response to cancer, and that systemic anticancer treatment can influence MSC levels. Further research is needed to determine whether MSCs have a predictive value.
What's new?
Mesenchymal Stem Cells (MSCs) can play a vital role in tumor progression and treatment response. MSCs interactions with tumors and their surroundings have been studied extensively, but little is known still about the role and fate of endogenously circulating MSCs in human cancer patients. This study is one of the first to detect endogenous MSC‐like cell populations in peripheral blood, and to demonstrate that this population is significantly increased in cancer patients. Systemic anti‐cancer treatment is associated with a sustained increase in circulating MSC‐like cells. The mechanisms behind this observation and its implications for anti‐cancer therapy remain to be elucidated.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized ...that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers.
In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency-approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks).
Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup.
Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.
To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with
mutations, regardless of histologic tumor type.
Patients with treatment-refractory
mutated cancer were ...included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive off-label drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model.
Twenty-four evaluable patients with nine different tumor types harboring
mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of
, while 73% of patients with biallelic
LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation,
amplification, and
loss, in three tumor types.
These data indicate that using PARPis is a promising treatment strategy for patients with non-
-associated histologies harboring biallelic
LoF. WGS allows to accurately detect complete LoF of
and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay.
Purpose
Chemotherapy-resistance remains a major obstacle to effective anti-cancer treatment. We previously showed that platinum analogs cause the release of two fatty acids. These platinum-induced ...fatty acids (PIFAs) induced complete chemoresistance in mice, whereas co-administration of a COX-1 inhibitor, indomethacin, prevented PIFA release and significantly enhanced chemosensitivity. To assess the safety of combining indomethacin with platinum-based chemotherapy, and to explore its efficacy and associated PIFA levels, a multi-center phase I trial was conducted.
Methods
The study was comprised of two arms: oxaliplatin plus capecitabine (CAPOX, arm I) and cisplatin plus gemcitabine, capecitabine or 5FU (arm II) in patients for whom these regimens were indicated as standard care. Indomethacin was escalated from 25 to 75 mg TID, using a standard 3 × 3 design per arm, and was administered orally 8 days around chemo-infusion from cycle two onwards. PIFA levels were measured before and after treatment initiation, with and without indomethacin.
Results
Thirteen patients were enrolled, of which ten were evaluable for safety analyses. In arm I, no dose-limiting toxicities were observed, and all indomethacin dose levels were well-tolerated. Partial responses were observed in three patients (30%). Indomethacin lowered plasma levels of 12-
S
-hydroxy-5,8,10-heptadecatrienoic acid (12-
S
-HHT), whereas 4,7,10,13-hexadecatetraenoic acid (16:4(n-3)) levels were not affected. Only one patient was included in arm II; renal toxicity led to closure of this cohort.
Conclusions
Combined indomethacin and CAPOX treatment is safe and reduces the concentrations of 12-
S
-HHT, which may be associated with improved chemosensitivity. The recommended phase II dose is 75 mg indomethacin TID given 8 days surrounding standard dosed CAPOX.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo ...systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAFV600E, NRASQ61, or BRAFWT/NRASWT melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAFV600E protein harboring a kinase domain duplication (BRAFV600E/DK) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAFV600E/DK depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAFV600E/DK-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.
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•Patient-derived xenograft (PDX) platform comprises 89 metastatic melanoma tumors•Platform includes several pre-vemurafenib and vemurafenib-resistant PDXs•Duplication of the BRAFV600E kinase domain is identified as a resistance mechanism•Pan-RAF dimerization inhibitor LY3009120 eliminates melanoma cells with this duplication
Kemper et al. have built a platform composed of 89 metastatic melanoma xenografts. Using this collection as a resource, they identified a BRAFV600E protein harboring a duplicated kinase domain. A pan-RAF dimerization inhibitor suppresses expansion of PDXs expressing this BRAF mutant.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Antineoplastic agents can provoke hyperglycemia in cancer patients with and without diabetes mellitus. We systematically reviewed the impact of hyperglycemia on the efficacy of ...chemotherapy. Methods MEDLINE was searched for preclinical intervention studies which compared chemotherapy response in hyperglycemic and euglycemic conditions. Results Thirteen preclinical studies, including 23 cell lines and 2 animal experiments were identified. In 14 cell lines and 2 animal studies, chemotherapy response was lower in a hyperglycemic (>15 mmol/L) compared to a euglycemic environment (5 mmol/L). The response was similar in 4 cell lines. In the remaining 5 cell lines, the hyperglycemic environment potentiated chemotherapy efficacy. Conclusion Hyperglycemia attenuated the antiproliferative effect of chemotherapy in preclinical experiments, but the results are inconsistent. Whether hyperglycemia influences efficacy of chemotherapy in patients needs to be explored.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo ...systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.
Full text
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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