Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy

Lee, Jin Ku; Liu, Zhaoqi; Jason, K.; Shin, Sang Hyun; Wang, Jiguang; Bordyuh, Mykola; Cho, Hee Jin; Elliott, Oliver; Chu, Timothy; Choi, Seung Won; Rosenbloom, Daniel I. S.; Lee, In-Hee; Shin, Yong Jae; Kang, Hyun Ju; Kim, Donggeon; Kim, Sun Young; Sim, Min Seob; Kim, Jusun; Lee, Taehyang; Seo, Yun Jee; Shin, Hong-Jae; Lee, Mijeong; Kim, Sung Heon; Kwon, Yong-Jun; Oh, Jeong-Woo; Song, Min‐Suk; Kim, Misuk; Kong, Doo‐Sik; Choi, Jung Won; Seol, Ho Jun; Lee, Jung-Il; Kim, Seung Tae; Park, Joon Oh; Kim, Kyoung‐Mee; Song, Sang‐Yong; Lee, Jeong‐Won; Kim, Hee Cheol; Lee, Jeong Eon; Choi, Min Gew; Seo, Sung Wook; Shim, Young Mog; Zo, Jae Ill; Jeong, Byong Chang; Yoon, Yong‐Ho; Ryu, Gyu Ha; Kim, Nayoung K.D.; Bae, Joon Seol; Park, Woong-Yang; Lee, Jeongwu; Verhaak, Roel G.W.; Iavarone, Antonio; Lee, Jeeyun; Rabadán, Raúl; Nam, Do‐Hyun

doi:10.1038/s41588-018-0209-6

Cited by 160 publications

(173 citation statements)

References 144 publications

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“…5), and economic ( Fig. 3B and C) [23][24][25][26][27][28][29][30][31][32] Kymriah (475,000 USD in US, 307,000 USD in Japan, 373,000 USD in UK), to establish a universal and viable therapeutic platform.…”

Section: Resultsmentioning

confidence: 99%

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Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

et al. 2019

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Section: Resultsmentioning

confidence: 99%

“…Cancer cells in the different region of the same primary tumor lesions are also genetically different [26]. Nearly 70% of all somatic mutations found on multiregional sequencing were geometrically heterogeneous and thus not detectable in every sequenced region [27].…”

Section: The Tumor-antigen Specificity and Mutationmentioning

confidence: 99%

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

et al. 2019

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“…To better address the clinical relevance of this hypothesis, we tested the correlation of RB1 protein level and BAY-876 sensitivity across a panel of TNBC patient derived samples. Patient-Derived Xenograft (PDX)-Derived Organoids (PDXDOs), which are thought to better recapitulate features of breast histology and epithelial heterogeneity, and therefore serve as better tools to assess drug responses for cancer therapy 43 . Thus, PDXDOs from five different TNBC patients were cultured, of which three cases are RB1-low, and two expressed RB1 based on immunoblots ( Fig.…”

Section: Pharmacological Inhibition Of Glut1 Impedes Tnbc Cancer Growmentioning

confidence: 99%

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

Ba-Alawi

Deblois

et al. 2019

Preprint

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Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data implicates E2F Targets pathway activity as a surrogate of OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) are strongly correlated with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.

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“…Short‐term and sustainable patient‐derived GBM cell cultures are indispensable and frequently used tools for basic research and therapy development (Fael Al‐Mayhani et al, ; Joo et al, ; Lee et al, ; Pollard et al, ). Before NSC media became the standard culture method, GBM cells were for decades established and maintained in serum‐containing media (Ponten & Macintyre, ), and many such GBM cell lines have been extensively used in research (Allen, Bjerke, Edlund, Nelander, & Westermark, ).…”

Section: Introductionmentioning

confidence: 99%

A molecularly distinct subset of glioblastoma requires serum‐containing media to establish sustainable bona fide glioblastoma stem cell cultures

Maturi

Tan

Xie

et al. 2019

Glia

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Glioblastoma (GBM) is the most frequent and deadly primary malignant brain tumor. Hallmarks are extensive intra‐tumor and inter‐tumor heterogeneity and highly invasive growth, which provide great challenges for treatment. Efficient therapy is lacking and the majority of patients survive less than 1 year from diagnosis. GBM progression and recurrence is caused by treatment‐resistant glioblastoma stem cells (GSCs). GSC cultures are considered important models in target identification and drug screening studies. The current state‐of‐the‐art method, to isolate and maintain GSC cultures that faithfully mimic the primary tumor, is to use serum‐free (SF) media conditions developed for neural stem cells (NSCs). Here we have investigated the outcome of explanting 218 consecutively collected GBM patient samples under both SF and standard, serum‐containing media conditions. The frequency of maintainable SF cultures (SFCs) was most successful, but for a subgroup of GBM specimens, a viable culture could only be established in serum‐containing media, called exclusive serum culture (ESC). ESCs expressed nestin and SOX2, and displayed all functional characteristics of a GSC, that is, extended proliferation, sustained self‐renewal and orthotopic tumor initiation. Once adapted to the in vitro milieu they were also sustainable in SF media. Molecular analyses showed that ESCs formed a discrete group that was most related to the mesenchymal GBM subtype. This distinct subgroup of GBM that would have evaded modeling in SF conditions only provide unique cell models of GBM inter‐tumor heterogeneity.

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Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy

Cited by 160 publications

References 144 publications

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

A molecularly distinct subset of glioblastoma requires serum‐containing media to establish sustainable bona fide glioblastoma stem cell cultures

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