Effective predictive biomarkers are needed to enable personalized medicine and increase treatment efficacy and survival for cancer patients, thereby reducing toxic side effects and treatment costs. ...Patient-derived organoids (PDOs) enable individualized tumour response testing. Since 2018, 17 publications have examined PDOs as a potential predictive biomarker in the treatment of cancer patients. We review and provide a pooled analysis of the results regarding the use of PDOs in individualized tumour response testing, focusing on evidence for analytical validity, clinical validity and clinical utility. We identify future perspectives to accelerate the implementation of PDOs as a predictive biomarker in the treatment of cancer patients.
Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy, including impairing the ability of chemotherapy-responsive tumors ...to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g., paclitaxel, can rapidly induce proangiogenic bone marrow-derived circulating endothelial progenitor (CEP) mobilization and subsequent tumor homing, whereas others, e.g., gemcitabine, do not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1α and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or paclitaxel treatment in CEP-deficient
Id mutant mice, both of which resulted in enhanced antitumor effects mediated by paclitaxel, but not by gemcitabine.
Recent studies suggest that chemotherapy, in addition to its cytotoxic effects on tumor cells, can induce a cascade of host events to support tumor growth and spread. Here, we used an experimental ...pulmonary metastasis model to investigate the role of this host response in metastasis formation. Mice were pretreated with chemotherapy and after clearance of the drugs from circulation, tumor cells were administered intravenously to study potential "protumorigenic" host effects of chemotherapy. Pretreatment with the commonly used chemotherapeutic agents cisplatin and paclitaxel significantly enhanced lung metastasis in this model. This corresponded to enhanced adhesion of tumor cells to an endothelial cell monolayer that had been pretreated with chemotherapy in vitro. Interestingly, chemotherapy exposure enhanced the expression of VEGF receptor 1 (VEGFR-1) on endothelial cells both in vitro and in vivo. Administration of antibodies targeting VEGFR-1 reversed the early retention of tumor cells in the lungs, thereby preventing the formation of chemotherapy-induced pulmonary metastases. The data indicate that chemotherapy-induced expression of VEGFR-1 on endothelial cells can create an environment favorable to tumor cell homing. Inhibition of VEGFR-1 function may therefore be used to counteract chemotherapy-induced retention of tumor cells within the metastatic niche, providing a novel level of tumor control in chemotherapy.
The determinants of metastasis in mismatch repair deficiency with high levels of microsatellite instability (MSI-H) in colorectal cancer (CRC) are poorly understood. Here, we hypothesized that ...distinct immune and stromal microenvironments in primary tumors may discriminate between non-metastatic MSI-H CRC and metastatic MSI-H CRC.
We profiled 46,727 single cells using high-plex imaging mass cytometry and analyzed both differential cell type abundance, and spatial distribution of fibroblasts and immune cells in primary CRC tumors with or without metastatic capacity. We validated our findings in a second independent cohort using immunohistochemistry.
High-plex imaging mass cytometry and hierarchical clustering based on microenvironmental markers separated primary MSI-H CRC tumors with and without metastatic capacity. Primary tumors with metastatic capacity displayed a high stromal content and low influx of CD8
T cells, which expressed significantly lower levels of markers reflecting proliferation (Ki67) and antigen-experience (CD45RO) compared to CD8
T cells in non-metastatic tumors. CD8
T cells showed intra-epithelial localization in non-metastatic tumors, but stromal localization in metastatic tumors, which was validated in a second cohort.
We conclude that localization of phenotypically distinct CD8
T cells within stroma may predict metastasis formation in MSI-H CRC.
Learning Objectives
After completing this course, the reader will be able to:
Describe the safety of using bevacizumab in clinical practice.
Explain the benefit of adding bevacizumab to chemotherapy ...in colorectal cancer.
Discuss mechanisms of targeting the VEGF/VEGFR pathway.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Vascular endothelial growth factor (VEGF) is one of the most important factors involved in tumor angiogenesis and has become an important target for anticancer treatment. In 2004, this approach was validated in a randomized, controlled phase III clinical trial. It was shown that the addition of bevacizumab, a humanized monoclonal antibody against VEGF‐A, to conventional chemotherapy prolonged survival over chemotherapy alone in patients with metastatic colorectal cancer. In this review, we discuss the results of the clinical trials that have led to the incorporation of antiangiogenic agents into the treatment of patients with advanced colorectal cancer. We limit ourselves to the two agents that have been tested extensively in phase III trials: bevacizumab and vatalanib, a small molecule tyrosine kinase inhibitor against VEGF receptors. In addition, we discuss the adverse effects of bevacizumab and vatalanib and the clinical management of the side effects.
Disclosure of potential conflicts of interest is found at the end of this article.
The development of resistance to chemotherapy is a major obstacle for lasting effective treatment of cancer. Here, we demonstrate that endogenous mesenchymal stem cells (MSCs) become activated during ...treatment with platinum analogs and secrete factors that protect tumor cells against a range of chemotherapeutics. Through a metabolomics approach, we identified two distinct platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)), that in minute quantities induce resistance to a broad spectrum of chemotherapeutic agents. Interestingly, blocking central enzymes involved in the production of these PIFAs (cyclooxygenase-1 and thromboxane synthase) prevents MSC-induced resistance. Our findings show that MSCs are potent mediators of resistance to chemotherapy and reveal targets to enhance chemotherapy efficacy in patients.
► Mesenchymal stem cells (MSCs) systemically induce resistance to chemotherapy ► Platinum-activated MSCs release two specific platinum-induced fatty acids (PIFAs) ► At minute quantities PIFAs induce resistance to various chemotherapeutics ► COX-1 and thromboxane synthase inhibition prevents MSC-induced resistance
Patient-derived organoids (PDOs) are widely heralded as a drug-screening platform to develop new anti-cancer therapies. Here, we use a drug-repurposing library to screen PDOs of colorectal cancer ...(CRC) to identify hidden vulnerabilities within therapy-induced phenotypes. Using a microscopy-based screen that accurately scores drug-induced cell killing, we have tested 414 putative anti-cancer drugs for their ability to switch the EGFRi/MEKi-induced cytostatic phenotype toward cytotoxicity. A majority of validated hits (9/37) are microtubule-targeting agents that are commonly used in clinical oncology, such as taxanes and vinca-alkaloids. One of these drugs, vinorelbine, is consistently effective across a panel of >25 different CRC PDOs, independent of RAS mutational status. Unlike vinorelbine alone, its combination with EGFR/MEK inhibition induces apoptosis at all stages of the cell cycle and shows tolerability and effective anti-tumor activity in vivo, setting the basis for a clinical trial to treat patients with metastatic RAS-mutant CRC.
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•Imaging-based screening on organoids enables scoring of drug-induced cell killing•Targeting MAPK signaling sensitizes colon cancers for microtubule-targeting agents•Combining MAPK pathway inhibition and vinorelbine is tolerable and effective in vivo•Induced cell killing by the combination therapy is independent of cell-cycle stage
Targeted therapies against KRAS-mutant colorectal cancers have proven to be problematic, whereby induction of cytotoxicity remains incomplete even upon effective suppression of downstream MAPK pathway activity. Mertens et al. find that effective inhibition of MAPK signaling sensitizes cancer cells for microtubule-targeting agents.
Metastatic breast cancer is the major cause of cancer-related death among women in the Western world. Invasive carcinoma cells are able to counteract apoptotic signals in the absence of anchorage, ...enabling cell survival during invasion and dissemination. Although loss of E-cadherin is a cardinal event in the development and progression of invasive lobular carcinoma (ILC), little is known about the underlying mechanisms that govern these processes. Using a mouse model of human ILC, we show here that cytosolic p120-catenin (p120) regulates tumor growth upon loss of E-cadherin through the induction of anoikis resistance. p120 conferred anchorage independence by indirect activation of Rho/Rock signaling through interaction and inhibition of myosin phosphatase Rho-interacting protein (Mrip), an antagonist of Rho/Rock function. Consistent with these data, primary human ILC samples expressed hallmarks of active Rock signaling, and Rock controlled the anoikis resistance of human ILC cells. Thus, we have linked loss of E-cadherin - an initiating event in ILC development - to Rho/Rock-mediated control of anchorage-independent survival. Because activation of Rho and Rock are strongly linked to cancer progression and are susceptible to pharmacological inhibition, these insights may have clinical implications for the development of tailor-made intervention strategies to better treat invasive and metastatic lobular breast cancer.
Adjuvant chemotherapy has been advised for high-risk stage II and III colon cancer since 2004. After the IDEA study showed no clinically relevant difference in outcome, reduction of adjuvant CAPOX ...duration from 6 to 3 months was rapidly adopted in the Dutch treatment guideline in 2017. This study investigates the real-world impact of the guideline change on overall survival (OS) and patient-reported outcomes (PROs).
Patients with high-risk stage II (pT4 +) and III (pN+) colon cancer were selected from the Netherlands Cancer Registry, based on surgical resection and adjuvant CAPOX before (2015–2016) versus after (2018–2019) the guideline change. Both groups were compared on OS, using multivariable Cox regression, and on PROs.
Patients treated before (n = 2330) and after (n = 2108) the guideline change showed similar OS (HR 1.02; 95 %CI 0.89–1.16), also in high-risk stage III (pT4/N2, HR 1.06 0.89–1.26). After the guideline change, 90 % of patients were treated for 3 months with no inferior OS to those still receiving 6 months (HR 0.89 0.66–1.20). PROs 2 years after CAPOX completion, available for a subset of patients, suggest a lower neuropathy (n = 366; 26.2 21.3–31.1 to 16.5 14.4–18.6) and better quality of life (n = 396; 80.9 78.6–83.2 to 83.9 82.8–84.9), but no significant difference in workability (n = 120; 31.5 27.9–35.1) to 35.3 33.8–36.7), with reduction from 6 to 3 months of CAPOX.
This real-world study confirmed that shorter adjuvant CAPOX did not compromise OS and may improve PROs, complementing the IDEA study and supporting 3 months of adjuvant CAPOX in daily clinical practice.
•Guideline change from 6 to 3 months of adjuvant CAPOX resembled a natural experiment.•Real-world overall survival before and after the guideline change was comparable.•Even in high-risk stage III colon cancer, survival was not worse after 3 months CAPOX.•Long-term neurotoxicity was lower and quality of life was better after 3 months CAPOX.
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