Evaluating the Role of Admixture in Cancer Therapy Via
            <i>in Vitro</i>
            Drug Response and Multivariate Genome-Wide Associations

Jack, John; Havener, Tammy M.; McLeod, Howard L.; Motsinger‐Reif, Alison A.; Foster, Matthew C.

doi:10.2217/pgs.15.85

Cited by 7 publications

(10 citation statements)

References 42 publications

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“…Of course, the response to anti-cancer agents and toxic chemicals is the measurable phenotype that associates with the residual Neanderthal variance in anatomically modern humans, but we hypothesize that Homo sapiens may have evolved resistance to a diverse array of phytochemicals due to a more heterogeneous diet relative to the predominantly meat-based diet of Neanderthals. Previous studies have shown the influence of race and ethnicity on the dose response phenotype ( Shord et al, 2006 ; Sharma, Cogswell & Li, 2008 ; Fu et al, 2014 ; Abdo et al, 2015 ; Jack et al, 2015 ). In this study, we show a strong association between Neanderthal ancestry and the dose response phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have shown strong differences in drug response in the LCL model for both pharmaceuticals and environmental chemicals. Differences in dose response phenotypes were observed between Hispanic and Caucasian populations for 28 chemotherapy drugs ( Jack et al, 2015 ) and significant variation in EC 10 was observed across the globally diverse populations from the 1000 Genomes Project (1000G) for 179 environmental chemicals ( Abdo et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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The influence of Neanderthal alleles on cytotoxic response

Akhtari

Havener

Fukudo

et al. 2018

PeerJ

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Various studies have shown that people of Eurasian origin contain traces of DNA inherited from interbreeding with Neanderthals. Recent studies have demonstrated that these Neanderthal variants influence a range of clinically important traits and diseases. Thus, understanding the genetic factors responsible for the variability in individual response to drug or chemical exposure is a key goal of pharmacogenomics and toxicogenomics, as dose responses are clinically and epidemiologically important traits. It is well established that ethnic and racial differences are important in dose response traits, but to our knowledge the influence of Neanderthal ancestry on response to xenobiotics is unknown. Towards this aim, we examined if Neanderthal ancestry plays a role in cytotoxic response to anti-cancer drugs and toxic environmental chemicals. We identified common Neanderthal variants in lymphoblastoid cell lines (LCLs) derived from the globally diverse 1000 Genomes Project and Caucasian cell lines from the Children’s Hospital of Oakland Research Institute. We analyzed the effects of these Neanderthal alleles on cytotoxic response to 29 anti-cancer drugs and 179 environmental chemicals at varying concentrations using genome-wide data. We identified and replicated single nucleotide polymorphisms (SNPs) from these association results, including a SNP in the SNORD-113 cluster. Our results also show that the Neanderthal alleles cumulatively lead to increased sensitivity to both the anti-cancer drugs and the environmental chemicals. Our results demonstrate the influence of Neanderthal ancestry-informative markers on cytotoxic response. These results could be important in identifying biomarkers for personalized medicine or in dissecting the underlying etiology of dose response traits.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The influence of Neanderthal alleles on cytotoxic response

Akhtari

Havener

Fukudo

et al. 2018

PeerJ

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“…iControl software (Version 1.11) was then used to measure the fluorescence intensity of resarufin at EX535nm and EM595nm. The resulting relative fluorescence units are proportional to cellular redox activity, which is a common proxy for the quantity of living cells 56 .…”

Section: Methodsmentioning

confidence: 99%

Synergistic drug combinations and machine learning for drug repurposing in chordoma

Anderson

Havener

Zorn

et al. 2020

Sci Rep

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Chordoma is a devastating rare cancer that affects one in a million people. With a mean-survival of just 6 years and no approved medicines, the primary treatments are surgery and radiation. In order to speed new medicines to chordoma patients, a drug repurposing strategy represents an attractive approach. Drugs that have already advanced through human clinical safety trials have the potential to be approved more quickly than de novo discovered medicines on new targets. We have taken two strategies to enable this: (1) generated and validated machine learning models of chordoma inhibition and screened compounds of interest in vitro. (2) Tested combinations of approved kinase inhibitors already being individually evaluated for chordoma. Several published studies of compounds screened against chordoma cell lines were used to generate Bayesian Machine learning models which were then used to score compounds selected from the NIH NCATS industry-provided assets. Out of these compounds, the mTOR inhibitor AZD2014, was the most potent against chordoma cell lines (ic 50 0.35 µM U-CH1 and 0.61 µM U-CH2). Several studies have shown the importance of the mtoR signaling pathway in chordoma and suggest it as a promising avenue for targeted therapy. Additionally, two currently FDA approved drugs, afatinib and palbociclib (EGFR and CDK4/6 inhibitors, respectively) demonstrated synergy in vitro (CI 50 = 0.43) while AZD2014 and afatanib also showed synergy (ci 50 = 0.41) against a chordoma cell in vitro. These findings may be of interest clinically, and this in vitro-and in silico approach could also be applied to other rare cancers. Chordoma is a rare cancer that occurs in the bones of the skull base and spine which is part of a larger class of tumors known as sarcomas. Chordoma tumors develop from cells of the notochord, an embryonic structure that facilitates development of the spine 1. The notochord disappears when the fetus is about 8 weeks old, but some notochord cells remain in the bones of the spine and skull base 2. This is a rare occurrence, but when they do, these cells can turn into chordoma. A chordoma tumor usually grows slowly without symptoms for years before diagnosis, which is often in the 5 th and 6 th decades of life (although it can occur at any age). Studies have demonstrated that skull base chordomas are observed more often in children, whilst spinal chordomas are more frequently observed later in life 2,3. It has also been described that when chordomas metastasize they frequently distribute to the lungs, liver, bones, or lymph nodes. This occurs in 30 to 40 percent of people where the tumor metastasizes to other parts of the body 2. At this point in time there are no known environmental, dietary or lifestyle risk factors for this rare type of cancer. Chordomas often occur at random with no direct inherited genetic trait, however familial cases can be caused by duplications of the brachyury gene 4. A SNP in the brachyury gene occurs in 95 percent of people with this tumor 5,6 , and furthermore, chordomas have ...

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“…These differences can be explained by genetic variation in ADME-related genes [93]. ADME-related genetic variability often differs across populations [94] and helps to explain the link between ancestry and variable chemotherapy drug response [95]. Li et al observed greater diversity in ADME genes for the African-American population compared with European and African populations [96], predisposing African-Americans to more variable drug response.…”

Section: Genomics and Epigenomics Of Symptoms And Chemotherapy Metabomentioning

confidence: 99%

Symptom Experience, Management, and Outcomes According to Race and Social Determinants Including Genomics, Epigenomics, and Metabolomics (SEMOARS + GEM): an Explanatory Model for Breast Cancer Treatment Disparity

et al. 2019

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Even after controlling for stage, comorbidity, age, and insurance status, black women with breast cancer (BC) in the USA have the lowest 5-year survival as compared with all other races for stage-matched disease. One potential cause of this survival difference is the disparity in cancer treatment, evident in many population clinical trials. Specifically, during BC chemotherapy, black women receive less relative dose intensity with more dose reductions and early chemotherapy cessation compared with white women. Symptom incidence, cancer-related distress, and ineffective communication, including the disparity in patientcenteredness of care surrounding patient symptom reporting and clinician assessment, are important factors contributing to racial disparity in dose reduction and early therapy termination. We present an evidence-based overview and an explanatory model for racial disparity in the symptom experience during BC chemotherapy that may lead to a reduction in dose intensity and a subsequent disparity in outcomes. This explanatory model, the Symptom Experience, Management, Outcomes and Adherence according to Race and Social determinants + Genomics Epigenomics and Metabolomics (SEMOARS + GEM), considers essential factors such as social determinants of health, clinician communication, symptoms and symptom management, genomics, epigenomics, and pharmacologic metabolism as contributory factors.

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Evaluating the Role of Admixture in Cancer Therapy Via in Vitro Drug Response and Multivariate Genome-Wide Associations

Cited by 7 publications

References 42 publications

The influence of Neanderthal alleles on cytotoxic response

The influence of Neanderthal alleles on cytotoxic response

Synergistic drug combinations and machine learning for drug repurposing in chordoma

Symptom Experience, Management, and Outcomes According to Race and Social Determinants Including Genomics, Epigenomics, and Metabolomics (SEMOARS + GEM): an Explanatory Model for Breast Cancer Treatment Disparity

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