Development of a precision medicine pipeline to identify personalized treatments for colorectal cancer

Altunel, Erdem; Roghani, Roham Salman; Chen, Kai-Yuan; Kim, So Young; McCall, Shannon J.; Ware, Kathryn E.; Shen, Xiling; Somarelli, Jason A.; Hsu, David S.

doi:10.1186/s12885-020-07090-y

Cited by 15 publications

(17 citation statements)

References 37 publications

(42 reference statements)

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“…The authors found a similar response to standard-of-care agents in the matched cell lines and PDX, allowing rapid analysis of sensitivity and resistance to standard-of-care agents. Moreover, from drug screening data, ponatinib, a multi-kinase inhibitor targeting several factors, including FGFR, platelet-derived growth factor receptor, vascular endothelial growth factor receptor, proto-oncogene tyrosine-protein kinases Src and Abl, was identified as a potentially effective therapeutic target for CRC for its action in inhibiting cell growth [ 105 ]. PDX model allows investigating the efficacy of the controversial anti-tumor agent.…”

Section: Patient-derived Modelsmentioning

confidence: 99%

Patient-derived tumor models: a more suitable tool for pre-clinical studies in colorectal cancer

Rizzo

Bertotti

Leto

et al. 2021

J Exp Clin Cancer Res

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Colorectal cancer (CRC), despite the advances in screening and surveillance, remains the second most common cause of cancer death worldwide. The biological inadequacy of pre-clinical models to fully recapitulate the multifactorial etiology and the complexity of tumor microenvironment and human CRC’s genetic heterogeneity has limited cancer treatment development. This has led to the development of Patient-derived models able to phenocopy as much as possible the original inter- and intra-tumor heterogeneity of CRC, reflecting the tumor microenvironment’s cellular interactions. Implantation of patient tissue into immunodeficient mice hosts and the culture of tumor organoids have allowed advances in cancer biology and metastasis. This review highlights the advantages and limits of Patient-derived models as innovative and valuable pre-clinical tools to study progression and metastasis of CRC, develop novel therapeutic strategies by creating a drug screening platform, and predict the efficacy of clinical response to therapy.

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Section: Patient-derived Modelsmentioning

confidence: 99%

Patient-derived tumor models: a more suitable tool for pre-clinical studies in colorectal cancer

Rizzo

Bertotti

Leto

et al. 2021

J Exp Clin Cancer Res

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“…Indeed, personalized medicine approaches for CRC that build on multiple ‘omics’ data and the use of patient-obtained biopsies are a promising way forward [ 215 , 216 ]. As a major step forward, recently a personalized medicine pipeline was developed, where patient-matched cell lines were used to identify new therapies and pathways to treat metastatic CRC [ 217 ].…”

Section: Discussionmentioning

confidence: 99%

Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage

Ternet

Kiel

2021

Cell Commun Signal

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The intestinal epithelium acts as a physical barrier that separates the intestinal microbiota from the host and is critical for preserving intestinal homeostasis. The barrier is formed by tightly linked intestinal epithelial cells (IECs) (i.e. enterocytes, goblet cells, neuroendocrine cells, tuft cells, Paneth cells, and M cells), which constantly self-renew and shed. IECs also communicate with microbiota, coordinate innate and adaptive effector cell functions. In this review, we summarize the signaling pathways contributing to intestinal cell fates and homeostasis functions. We focus especially on intestinal stem cell proliferation, cell junction formation, remodelling, hypoxia, the impact of intestinal microbiota, the immune system, inflammation, and metabolism. Recognizing the critical role of KRAS mutants in colorectal cancer, we highlight the connections of KRAS signaling pathways in coordinating these functions. Furthermore, we review the impact of KRAS colorectal cancer mutants on pathway rewiring associated with disruption and dysfunction of the normal intestinal homeostasis. Given that KRAS is still considered undruggable and the development of treatments that directly target KRAS are unlikely, we discuss the suitability of targeting pathways downstream of KRAS as well as alterations of cell extrinsic/microenvironmental factors as possible targets for modulating signaling pathways in colorectal cancer.

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“…High-throughput drug screening. High-throughput screens were performed in collaboration with the Duke Functional Genomics Shared Resource as previously described [34][35][36][37]. Briefly, compounds from the Bioactives library (SelleckChem) were stamped in triplicate into 384-well plates at a final concentration of 1 μM using an Echo Acoustic Dispenser (Labcyte, Indianapolis, IN, USA).…”

Section: Methodsmentioning

confidence: 99%

A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer

Ware

Thomas

Olawuni

et al. 2022

Preprint

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Despite substantial improvements in the treatment landscape of prostate cancer, the evolution of hormone therapy-resistant and metastatic prostate cancer remains a major cause of cancer-related death globally. The mainstay of treatment for advanced prostate cancer is targeting of androgen receptor signaling, including androgen deprivation therapy plus second-generation androgen receptor blockade (e.g., enzalutamide, apalutamide, darolutamide), and/or androgen synthesis inhibition (abiraterone). While these agents have significantly prolonged the lives of patients with advanced prostate cancer, the evolution of resistance to these treatments in nearly universal. This therapy resistance is mediated by diverse mechanisms, including both androgen receptor-dependent mechanisms, such as androgen receptor mutations, amplifications, alternative splicing, and amplification, as well as non-androgen receptor-mediated mechanisms, such as lineage plasticity toward neuroendocrine-like or epithelial-mesenchymal transition (EMT)-like lineages. Our prior work identified the EMT transcriptional regulator Snail as critical to hormonal therapy resistance and is commonly detected in human metastatic prostate cancer. In the current study, we sought to interrogate the actionable landscape of EMT-mediated hormone therapy resistant prostate cancer to identify synthetic lethality and collateral sensitivity approaches to treating this aggressive, therapy-resistant disease state. Using a combination of high-throughput drug screens and multi-parameter phenotyping by confluence imaging, ATP production, and phenotypic plasticity reporters of EMT, we identified candidate synthetic lethalities to Snail-mediated EMT in prostate cancer. These analyses identified multiple actionable targets, such as XPO1, PI3K/mTOR, aurora kinases, c-MET, polo-like kinases, and JAK/STAT as synthetic lethalities in Snail+ prostate cancer. We validated these targets in a subsequent validation screen in an LNCaP-derived model of resistance to sequential androgen deprivation and enzalutamide. This follow-up screen provided validation of inhibitors of JAK/STAT and PI3K/mTOR as therapeutic vulnerabilities for both Snail+ and enzalutamide-resistant prostate cancer.

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Development of a precision medicine pipeline to identify personalized treatments for colorectal cancer

Cited by 15 publications

References 37 publications

Patient-derived tumor models: a more suitable tool for pre-clinical studies in colorectal cancer

Patient-derived tumor models: a more suitable tool for pre-clinical studies in colorectal cancer

Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage

A synthetic lethal screen for Snail-induced enzalutamide resistance identifies JAK/STAT signaling as a therapeutic vulnerability in prostate cancer

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