Patient-derived tumor xenograft models for melanoma drug discovery

Harris, Ann; Joseph, Richard W.; Copland, John A.

doi:10.1080/17460441.2016.1216968

Cited by 17 publications

(17 citation statements)

References 84 publications

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“…A primary cause of marginal advancements of new agents in oncology is due to lack of preclinical models that recapitulate patient tumor heterogeneity [ 11 ]. The complex genetic alterations involved in metastatic melanoma progression require preclinical models to better understand its biology to conceptualize novel combination therapies [ 12 ] leading to drug efficacy in humans. PDTX models are considered reliable preclinical models due to their ability to predict clinical activity, mimic patient response to therapy [ 13 ], maintain key genes and global pathway activity as that of patients’ tumors [ 14 ], possess tumor heterogeneity, and investigate novel therapeutic compounds.…”

Section: Introductionmentioning

confidence: 99%

Targeting the cyclin dependent kinase and retinoblastoma axis overcomes standard of care resistance in BRAFV600E-mutant melanoma

Harris

Lee²,

Dawson³

et al. 2017

Oncotarget

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Patient-derived tumor xenograft (PDTX) mouse models were used to discover new therapies for naïve and drug resistant BRAFV600E-mutant melanoma. Tumor histology, oncogenic protein expression, and antitumor activity were comparable between patient and PDTX-matched models thereby validating PDTXs as predictive preclinical models of therapeutic response in patients. PDTX models responsive and non-responsive to BRAF/MEK standard of care (SOC) therapy were used to identify efficacious combination therapies. One such combination includes a CDK4/6 inhibitor that blocks cell cycle progression. The rationale for this is that the retinoblastoma protein (pRb) is 95% wildtype in BRAF mutant melanoma. We discovered that 77/77 stage IV metastatic melanoma tissues were positive for inactive phosphorylated pRb (pRb-Ser780). Rb is hyperphosphorylated and inactivated by CDK4/6:cyclin D1 and when restored to its hypophosphorylated active form blocks cell cycle progression. The addition of a CDK4/6 inhibitor to SOC therapy was superior to SOC. Importantly, triple therapy in an upfront treatment and salvage therapy setting provided sustained durable response. We also showed that CDK4/6 blockade resensitized drug resistant melanoma to SOC therapy. Durable response was associated with sustained suppression of pRb-Ser780. Thus, reactivation of pRb may prove to be a clinical biomarker of response and the mechanism responsible for durable response. In light of recent clinical trial data using this triple therapy against BRAFV600E-mutant melanoma, our findings demonstrating superior and prolonged durable response in PDTX models portend use of this therapeutic strategy against naïve and SOC resistant BRAF V600E-mutant metastatic melanoma coupled with pRB-Ser780 as a biomarker of response.

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Section: Introductionmentioning

confidence: 99%

Targeting the cyclin dependent kinase and retinoblastoma axis overcomes standard of care resistance in BRAFV600E-mutant melanoma

Harris

Lee²,

Dawson³

et al. 2017

Oncotarget

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“…Future studies will investigate further advantages of the melanoma PDOX model. Please see references [ 78 , 79 ] for reviews of melanoma PDX models. Future studies will address molecular changes in the treated melanoma PDOX models described in the present report.…”

Section: Resultsmentioning

confidence: 99%

Patient-Derived Orthotopic Xenograft (PDOX) Models of Melanoma

Hoffman

2017

IJMS

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Metastatic melanoma is a recalcitrant tumor. Although “targeted” and immune therapies have been highly touted, only relatively few patients have had durable responses. To overcome this problem, our laboratory has established the melanoma patient-derived orthotopic xenograft (PDOX) model with the use of surgical orthotopic implantation (SOI). Promising results have been obtained with regard to identifying effective approved agents and experimental therapeutics, as well as combinations of the two using the melanoma PDOX model.

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“…Authors report PDX generated for nonsmall cell lung carcinoma closely mimics the characteristics of patient primary tumors [120,121], lung squamous cell carcinoma [122], and colorectal cancer [123]. Data are also available for renal cell carcinoma [124], melanoma [125], gastric [126], breast [127], and other cancers.…”

Section: In Vivo Modelsmentioning

confidence: 99%

Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

Stulpinas¹,

Imbrasaitė²,

Krestnikova³

et al. 2020

Tumor Progression and Metastasis

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Despite the advancements in biomarker-based personalized cancer therapy, the inadequacy of molecular and genetic profiling in identifying effective drug combinations was defined in most cases. Drug resistance remains a major limitation of the current predictive oncology. Emerging reports indicate that the success of anticancer therapy is usually limited by intratumoral heterogeneity which is not captured by the existing cancer cell biomarker-based approaches. Cell heterogeneity, not only genetic but also phenotypic, is considered to be the root cause of resistance to anticancer treatment, cancer progression, and the presence of cancer stem cells. Therefore, functional testing of live cells representing various cell types within the tumor exposed to potential therapies is needed for identification of effective drug combinations. Here we look at the different existing model systems, including ex vivo models of the patient's tumor cells, 2D/3D in vitro cultures/cocultures, patient-derived cellular organoids, single-cell models, ex vivo tumor platforms containing tumor microenvironment and extracellular matrix, etc., scoping at drug efficacy evaluation and solving the problem of cancer resistance.

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Patient-derived tumor xenograft models for melanoma drug discovery

Cited by 17 publications

References 84 publications

Targeting the cyclin dependent kinase and retinoblastoma axis overcomes standard of care resistance in BRAFV600E-mutant melanoma

Targeting the cyclin dependent kinase and retinoblastoma axis overcomes standard of care resistance in BRAFV600E-mutant melanoma

Patient-Derived Orthotopic Xenograft (PDOX) Models of Melanoma

Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

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