Precision Medicine In Treatment Research Articles

Abstract PD10-05: Universal genetic testing in breast cancer patients: A multi-center prospective study

Abstract Background: Hereditary factors play a key role in the risk of developing breast cancers. Identification of a germline predisposition can have important implications for treatment decisions, risk-reducing interventions, cancer screening, and testing for family members. Aim: To determine the prevalence of pathogenic or likely pathogenic germline mutations (P/LP) using a “universal” testing approach and uptake of no-cost cascade family testing in patients with breast cancer. Methods: We undertook a prospective multi-site study of germline genetic alterations among breast cancer patients receiving care at Mayo Clinic cancer centers in Rochester, MN; Eau Claire, WI; Jacksonville, FL and Phoenix, AZ between April 1, 2018 and March 31, 2020. Patients with a new or active breast cancer diagnosis (all stages) irrespective of cancer family history were tested with a >80-gene next generation sequencing panel.Results: Of 390 patients, the median age was 58 years (SD 12.3), 1% were male, 85% were white and 28% had advanced (stage 3-4) disease. P/LP were found in 12.1% (n=47) of patients, including 29 in moderate and high penetrance cancer susceptibility genes. 13 (3.3%) patients had mutations in BRCA1 or 2, while 33 (8.4%) had mutations in BRCAness (ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C, RAD51D, WRN) associated genes. Of the P/LP findings the most frequent aberrations were in BRCA2 (13.5%), BRCA1 (11.5%), CHEK2 (11.5%), MUTYH (11.5%), and WRN (9.6%). Variants of uncertain significance were found in 209 (53.6%) including 26 (6.6%) with concurrent P/LP and VUS. 37 (9.4%) patients had mutations associated with published management recommendations, precision therapies and/or clinical trial eligibility. 10 (2.6%) patients had P/LP that would not have met current screening guidelines, including 4 with moderate or high penetrance mutations. Patients with younger age of diagnosis were less likely than patients with older age of diagnosis to have a P/LP mutation (OR= 0.47, 95%CI: 0.25-0.90 p = 0.020). Only 10 (21%) patients with P/LP had family members undergo familial site- specific testing at no cost.Conclusions: In this prospective multi-center study of unselected breast cancer patients, universal multi-gene panel testing found that 1 in 8 patients harbor P/LP germline variants. Current guidelines were able to identify the majority of patients with P/LP mutations. Familial site specific testing is greatly under-utilized even when cost is not a barrier. Multigene panels impact cancer patient care by identifying precision medicine treatment interventions, and guiding long-term medical management and preventive surveillance. Citation Format: Brenda Ernst, Natalie Ertz-Archambault, Deborah J Rhodes, Donald W Northfelt, Myra Wick, Douglas L Riegert-Johnson, Scott Okuno, Katie Kunze, Michael Golafshar, Cindy M Azevedo, PLS Uson Junior, ED Esplin, Robert Nussbaum, Margaret Klint, Sarah Mantia, Megan Hager, Keith Stewart, Niloy Jewel Samadder. Universal genetic testing in breast cancer patients: A multi-center prospective study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-05.

Differential Inhibition of LRRK2 in Parkinson's Disease Patient Blood by a G2019S Selective LRRK2 Inhibitor.

ABSTRACTBackgroundA common genetic mutation that causes Parkinson's disease (PD) is the G2019S LRRK2 mutation. A precision medicine approach that selectively blocks only excess kinase activity of the mutant allele could yield a safe and effective treatment for G2019S LRRK2 PD.ObjectiveTo determine the activity of a G2019S mutant selective leucine‐rich repeat kinase 2 (LRRK2) kinase inhibitor as compared to a nonselective inhibitor in blood of subjects with genetic and idiopathic PD on two LRRK2 biomarkers, pSer935 LRRK2 and pThr73 Rab10.MethodsBlood was collected from 13 subjects with or without a G2019S LRRK2 mutation with PD and one healthy control. Peripheral blood mononuclear cells were treated ex vivo with a novel G2019S LRRK2 inhibitor (EB‐42168) or the nonselective inhibitor MLi‐2. Quantitative western immunoblot analyses were performed.ResultsEB‐42168 was 100 times more selective for G2019S LRRK2 when compared to wild‐type (WT) LRRK2. Concentrations that inhibited phosphorylation of pSer935 LRRK2 by 90% in homozygous G2019S LRRK2 patients, inhibited pSer935 LRRK2 by 36% in heterozygous patients, and by only 5% in patients carrying only the WT allele. Similar selectivity was seen for pThr73 Rab10. MLi‐2 showed an equivalent level of inhibition across all genotypes.ConclusionsThese findings demonstrate that EB‐42168, a G2019S LRRK2 selective inhibitor, lowers mutant G2019S LRRK2 phosphorylated biomarkers while simultaneously sparing WT LRRK2. Selective targeting of G2019S LRRK2 with a small molecule lays the foundation for a precision medicine treatment of G2019S LRRK2 PD. © 2021 ESCAPE Bio, Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Whole-exome Sequencing of Tumor-only Samples Reveals the Association between Somatic Alterations and Clinical Features in Pancreatic Cancer

Background: Identification of genomic markers using NGS (next-generation sequencing) technology would be valuable for guiding precision medicine treatments for pancreatic cancers. Traditional somatic mutation methods require both tumor and matched non-tumor samples. However, only tumor samples are available mostly, especially in retrospective studies. In this study, we tried to analyze the associations between clinical features and oncogenic somatic mutations in genome-wide tumor-only samples. Methods: Fifty-four tumor-only samples derived from pancreatic cancer patients were used for whole-exome sequencing. An approach involving SNP filtering of variants included in the Catalogue of Somatic Mutations in Cancer (COSMIC) database was used to identify oncogenic somatic mutations. The relationships between oncogenic mutations and clinical features were analyzed and simultaneously compared with those from the TCGA database. Results: By analyzing the mutations from tumor only samples, divergent mutation profiles were observed in different locations (head vs. body/tail) of pancreatic tumors. The divergences between pancreatic head and body/tail cancers were also confirmed by the TCGA data. Furthermore, mutations of several genes were found to be significantly associated with clinical features, such as pathological stage and the degree of tumor differentiation. Conclusion: The results confirmed the efficiency of our approach in identifying oncogenic somatic mutations from tumor only samples and revealed the associations between somatic mutations and clinical features in pancreatic cancer.

Immunology and Immunopathology of COVID-19: Precision Medicine and Individualized Treatment Approach are Decisive Factors

As I noted in my previous editorial, It is necessary to examine the immunological aspects of COVID-19. Thus, in order to identify the underlying mechanisms, design appropriate treatment protocols, and effective vaccination, we started to conduct a multicenter cohort study entitled “Iran-Cohort Study of COVID-19 Immunology and Immunopathology”. This comprehensive multicenter cohort study is underway at Immunoregulation Research Center, Shahed University, Tehran, Iran.

Understanding stakeholder awareness and communication strategies to inform implementation of precision medicine among minority populations: a systematic review

This systematic review aimed to 1) understand Stakeholder Awareness of benefits, risks, and likelihood of participating in precision medicine research and treatment and 2) identify effective Communication Strategies to increase awareness of precision medicine. Read more at JCTRes.com

Frailty Worsens Antidepressant Treatment Outcomes in Late Life Depression

ObjectiveTo investigate the relationship between frailty and treatment response to antidepressant medications in adults with late life depression (LLD). MethodsData were evaluated from 100 individuals over age 60 years (34 men, 66 women) with a depressive diagnosis, who were assessed for frailty at baseline (characteristics include gait speed, grip strength, activity levels, fatigue, and weight loss) and enrolled in an 8-week trial of antidepressant medication followed by 10 months of open-treatment. ResultsFrail individuals (n = 49 with ≥3 deficits in frailty characteristics) did not differ at baseline from the non/intermediate frail (n = 51 with 0–2 deficits) on demographic, medical comorbidity, cognitive, or depression variables. On average, frail individuals experienced 2.82 fewer Hamilton Rating Scale for Depression (HRSD) points of improvement (t = 2.12, df 89, p = 0.037) than the non/intermediate frail over acute treatment, with this difference persisting over 10 months of open-treatment. Weak grip strength and low physical activity levels were each associated with decreased HRSD improvement, and lower response and remission rates over the course of the study. Despite their poorer outcomes, frail individuals received more antidepressant medication trials than the non/intermediate frail. ConclusionAdults with LLD and frailty have an attenuated response to antidepressant medication and a greater degree of disability compared to non/intermediate frail individuals. This disability and attenuated response remain even after receiving a greater number of antidepressant medication trials. Future research must focus on understanding the specific pathophysiology associated with the frail-depressed phenotype to permit the design and implementation of precision medicine interventions for this high-risk population.

Subcellular Organization of the cAMP Signaling Pathway.

The field of cAMP signaling is witnessing exciting developments with the recognition that cAMP is compartmentalized and that spatial regulation of cAMP is critical for faithful signal coding. This realization has changed our understanding of cAMP signaling from a model in which cAMP connects a receptor at the plasma membrane to an intracellular effector in a linear pathway to a model in which cAMP signals propagate within a complex network of alternative branches and the specific functional outcome strictly depends on local regulation of cAMP levels and on selective activation of a limited number of branches within the network. In this review, we cover some of the early studies and summarize more recent evidence supporting the model of compartmentalized cAMP signaling, and we discuss how this knowledge is starting to provide original mechanistic insight into cell physiology and a novel framework for the identification of disease mechanisms that potentially opens new avenues for therapeutic interventions.Significance StatementcAMP mediates the intracellular response to multiple hormones and neurotransmitters. Signal fidelity and accurate coordination of a plethora of different cellular functions is achieved via organization of multiprotein signalosomes and cAMP compartmentalization in subcellular nanodomains. Defining the organization and regulation of subcellular cAMP nanocompartments is necessary if we want to understand the complex functional ramifications of pharmacological treatments that target G protein–coupled receptors and for generating a blueprint that can be used to develop precision medicine interventions.

Application Research of Precision Medical Model Based on Big Data in Primary Health Care in China

Abstract In this paper, relevant literatures on precision medicine and primary health care under big data from 2005 to 2020 were selected on CNKI, Wanfang Data Knowledge Service Platform, PUBMED and so on. A total of 98 literatures were included to summarize the development, difficulties and suggestions on precision medicine in China. This paper analyzes the application of precision medicine in China’s primary health care and the technical and social problems that precision medicine faces in the era of big data, and puts forward the next research direction of community precision medicine prevention and treatment. Conclusion,: the application of precision medicine in primary health care is still in its infancy. Genomic data, sample management, data quality control standards and data management platform construction are the foundation of community precision medicine. “Intelligent precision medicine” will be the future development direction.

Clinical Outcome-Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma.

Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of etiology and identify the potential prognostic biomarkers. We performed an integrative genomic analysis for a total of 731 nasopharyngeal carcinoma cases from five independent nasopharyngeal carcinoma cohorts to identify the genetic events associated with clinical outcomes. In addition to the known mutational signatures associated with aging, APOBEC and mismatch repair (MMR), a new signature for homologous recombination deficiency (BRCAness) was discovered in 64 of 216 (29.6%) cases in the discovery set including three cohorts. This signature appeared more frequently in the recurrent and metastatic tumors and significantly correlated with shorter overall survival (OS) in the primary tumors. Independent prognostic value of MMR and BRCAness signatures was revealed by multivariable Cox analysis after adjustment for clinical parameters and stratification by studies. The cases with both signatures had much worse clinical outcome than those without these signatures [hazard ratio (HR), 12.4; P = 0.002]. This correlation was confirmed in the validation set (HR, 8.9; P = 0.003). The BRCAness signature is highly associated with BRCA2 pathogenic germline or somatic alterations (7.8% vs. 0%; P = 0.002). Targeted sequencing results from a prospective nasopharyngeal carcinoma cohort (N = 402) showed that the cases carrying BRCA2 germline rare variants are more likely to have poor OS and progression-free survival. Our study highlights importance of defects of DNA repair machinery in nasopharyngeal carcinoma pathogenesis and their prognostic values for clinical implications. These signatures will be useful for patient stratification to evaluate conventional and new treatment for precision medicine in nasopharyngeal carcinoma.

Abstract PO-128: Interrogating the role of race-related alternative splicing of SEMA3C in prostate cancer

Abstract The age-adjusted incidence and mortality rates for prostate cancer (PCa) among African American (AA) men are 1.6- and 2.4-fold greater, respectively, than among white men. These disparities likely result from a complex interplay among social, psycho-social, lifestyle, environmental, health system, and biological determinants of health. Despite the contribution of biological determinants of health, very few studies have utilized this population-based difference to identify the molecular mechanisms underlying race-related tumor aggressiveness. We have previously identified Semaphorin 3C (SEMA3C) as a novel alternatively spliced gene in PCa between AA and white patients. SEMA3C has been shown to be associated with increased cancer growth, poor prognosis in lung, breast, gastric, and ovarian cancers, and promotion of cell migration and invasion in PCa. To further study the significance of race-related skipping/inclusion of SEMA3C exon 19 in PCa cell biology, we used CRISPR/Cas9 technology to engineer a PCa cell line (DU145) expressing the SEMA3C variant skipping exon 19. Proliferation assays were performed with the established cell lines, and the SEMA3C exon 19 KO populations exhibited decreased proliferation rates, compared with the wild-type DU145 cells that express the SEMA3C variant including exon 19. These data suggest race-related alternative splicing of SEMA3C may have an impact on PCa aggressiveness in patients. Current and future experiments focus on interrogating the effect of race-related SEMA3C alternative splicing on PCa cell migration and invasion as well as in vivo tumor formation and metastasis. These findings will provide an increased understanding of the role of race-related alternative splicing in PCa disparities and potentially a new target for development of precision medicine interventions. Citation Format: Tyler A. Allen, Jay Chandar, Bonnie L. Lacroix, Steven R. Patierno, Daniel J. George, Jennifer A. Freedman. Interrogating the role of race-related alternative splicing of SEMA3C in prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-128.

Abstract PR15: CanSplice: A user-friendly web application for analysis of genomic datasets by race and ethnicity

Abstract The rate of cancer incidence and mortality differ in populations of different ancestry. Comparative analyses of cancer specimens have identified race- and ethnicity-related differential mutation spectra and gene expression, RNA splicing, and epigenetic patterns. These findings suggest that race- and ethnicity-related molecular mechanisms have the potential to contribute to cancer aggressiveness in individuals of different racial and ethnic groups. Advances in technology have enabled researchers to perform high-throughput genome-wide analyses of cancer specimens, including of the exome, transcriptome, proteome, and methylome. Such analyses have generated large amounts of data, which can be challenging for many cancer researchers to analyze. In addition, although many user-friendly tools have been developed for mining big data, there is an urgent need for tools that enable the mining of big data by patient race and ethnicity. Here, we developed a user-friendly online application, CanSplice, that enables the cancer disparity research community to interactively navigate and visualize genomic datasets and perform comparative and correlative analyses. Additionally, researchers using CanSplice can evaluate the association between genomics and patient survival probability in the context of patient race and ethnicity. Uniquely, CanSplice enables exploration of RNA splicing datasets by race and ethnicity and analysis of the association between a given RNA splicing event and patient survival probability. Currently, CanSplice includes data from The Cancer Genome Atlas (TCGA) and TCGASpliceSeq; however, new data from additional cohorts will be added continuously. In conclusion, CanSplice is a user-friendly online application that enables innovative exploration of publicly available cancer genomic datasets by patient race and ethnicity for hypothesis generation. Identified targets can then be validated and investigated for functionality in the laboratory. Thus, data from CanSplice will further understanding of molecular mechanisms underlying cancer disparities and has the potential to aid in the development of novel precision medicine interventions to mitigate cancer disparities. Citation Format: Muthana Al Abo, Steven R. Patierno, Jennifer A. Freedman. CanSplice: A user-friendly web application for analysis of genomic datasets by race and ethnicity [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PR15.

Competing endogenous RNAs and cancer: How coding and non-coding molecules cross-talk can impinge on disease.

Cancers are characterized by several dramatic biological changes. Among the many post-transcriptional regulatory mechanisms, microRNAs are known as fine-tune regulators for their transcript silencing ability. Competing endogenous RNAs (ceRNAs) are transcripts that share microRNA binding elements and can compete for them, thus regulating each other indirectly. ceRNA networks interconnect the regulatory control of different transcript classes of the coding and non-coding space and co-operate with other cellular and molecular regulatory mechanisms. Altered ceRNA networks are involved in tumor formation and progression as well as in chemoresistance, in invasion and in the onset of metastases. The analysis of changes in the balance between ceRNA transcripts could offer hints to identify novel pathways for diagnosis, prognosis and therapies in precision medicine interventions. Moreover, the possibility to query highly specific tumor databases, such as TCGA, and to combine clinical data, transcript expression and sequence information is allowing to develop specific predictive tools for precision medicine.

Awareness about Precision Medicine among Dental Students: A Survey

Precision medicine is a method of prevention and treatment which is based on biological databases. Precision medicine has been used in existence for more than a century. More than one million people have contributed their data to precision medicine. This study focuses especially to evaluate the knowledge on characteristics of precision medicine​. The aim of this study is to create awareness of Precision medicine among dental students. Based on a cross-sectional study, a survey was conducted among dental students on precision medicine. The questionnaire was distributed through an online survey link (i.e.) google forms. Nearly 150 students participated in it. Data was circulated, results were collected and statistically analysed through spss software. 97.6% of the people are mostly aware of precision medicine, where 47% are male and 53 % are female. 77.1% of the people are aware that the precision medicine treatment is based on DNA and it’s genetic variations. 75.3% of people feel that precision medicine is not affordable by everyone. This study was made to improve the awareness and knowledge of precision medicine in dentistry.

Strategies to minimize preventable morbidity and mortality resulting from pandemics like COVID-19.

Strategies to minimize preventable morbidity and mortality resulting from pandemics like COVID-19.

Precision Medicine: Steps along the Road to Combat Human Cancer.

The diagnosis and treatment of diseases such as cancer is becoming more accurate and specialized with the advent of precision medicine techniques, research and treatments. Reaching down to the cellular and even sub-cellular level, diagnostic tests can pinpoint specific, individual information from each patient, and guide providers to a more accurate plan of treatment. With this advanced knowledge, researchers and providers can better gauge the effectiveness of drugs, radiation, and other therapies, which is bound to lead to a more accurate, if not more positive, prognosis. As precision medicine becomes more established, new techniques, equipment, materials and testing methods will be required. Herein, we will examine the recent innovations in assays, devices and software, along with next generation sequencing in genomics diagnostics which are in use or are being developed for personalized medicine. So as to avoid duplication and produce the fullest possible benefit, all involved must be strongly encouraged to collaborate, across national borders, public and private sectors, science, medicine and academia alike. In this paper we will offer recommendations for tools, research and development, along with ideas for implementation. We plan to begin with discussion of the lessons learned to date, and the current research on pharmacogenomics. Given the steady stream of advances in imaging mass spectrometry and nanoLC-MS/MS, and use of genomic, proteomic and metabolomics biomarkers to distinguish healthy tissue from diseased cells, there is great potential to utilize pharmacogenomics to tailor a drug or drugs to a particular cohort of patients. Such efforts very well may bring increased hope for small groups of non-responders and those who have demonstrated adverse reactions to current treatments.

CircRNA CircRIMS Acts as a MicroRNA Sponge to Promote Gastric Cancer Metastasis.

Circular RNAs (circRNAs), a new category of noncoding RNA, have emerged in recent years as novel biomolecules with important biological functions. Increasing evidence and reports have revealed that circRNAs play an important role in human carcinogenesis and tumor progression. Gastric cancer (GC) is one of the most prevalent life-threatening malignancies worldwide, and in the present study, a novel circRNA molecule (circRIMS) was shown to be associated GC metastasis using next-generation sequencing. CircRIMS remarkably promoted GC cell metastasis in vitro, functioning as a sponge for hsa-miR-148a-5p and hsa-miR-218-5p. In addition, the results of rescue experiments showed that hsa-miR-148a-5p and hsa-miR-218-5p mimics could reverse the tumor-promoting roles of circRIMS in GC. Thus, circRIMS has potential as an early biomarker for use in predicting invasive metastasis in GC and to guide clinical diagnosis and treatment for precision medicine.

Abstract 3620: Actionable genomic landscape of metastatic colorectal cancer patients in Korea: Interim data from K-MASTER project

Abstract The K-MASTER cancer precision medicine diagnosis and treatment enterprise (K-MASTER project) is a precision medicine cancer treatment clinical trial platform, which uses NGS assay to screen the actionable mutations in 10,000 Korean patients with refractory solid tumors and assigns the patients to matched clinical trials. K-MASTER project was initiated at June 2017 and 52 sites, 4930 patients have participated. As of November 30 in 2019, total 889 metastatic colorectal cancer (mCRC) patients were submitted. Tumor DNA was analyzed by FIRST cancer panel (Seoul National University Hospital) and CancerSCAN (Samsung Genomic Institute) which allow to detect variations of 183 and 409 genes irrespectively. The failure rate of sequencing was 5.5% of patients with samples submitted. The mean depth was 650x (FIRST) and 701x (CancerSCAN). Average turn-around time was 3 weeks (CancerScan) and 6 weeks (FIRST). In Korean mCRC patients, variations were mainly identified in TP53 (60.9%), APC (56.9%), KRAS (41.4%), BRCA2 (19.2%), PIK3CA (14.5%), ATM (14.2%), KMT2D (13.4%), NOTCH1(13.4%), SMAD4 (11.6%), FBXW7 (10.2%), ALK (9.7%), NOTCH3 (9.2%), BRAF (8.8%). MSI-high or POLE mutant mCRC patients were enrolled in KM-01 (Avelumab). Several drugs were already approved in the other countries but not in Korea; ERBB (7.5%) with anti-HER2 agents, and MSI high such as MSH6 (3.9%), MSH2 (3.7%), MLH1 (3.4%) with immune checkpoint inhibitors. In addition, there were potentially actionable variants outside of approved label in Korea; translocation of NTRK3 (n=4), RET (n=3), ALK/EML4 (n=2). Promising drugs could be possible to incorporate in clinical trials using PIK3CA (14.5%) with PIK3CA/Akt/mTOR pathway inhibitor, DNA damage response (DDR) genes such as BRCA2 (19.2%), ATM (14.2%), FANCA (6.6%), POLE (5.8%), BRIP1(4.8%), RAD50 (4.5%), BRCA(4.0%), PALB2 (4.0%), PARP2 (3.7%), CDK12 (3.4%), MUTYH (2.7%), RAD54L (2.5%) with immune checkpoint inhibitor and/or PARP inhibitor, KRAS G12C (n=18) with AMG 510 (KRAS inhibitor), amplification of FGFR1 (n=4) and MET (n=1). There are 2 clinical trials which mCRC patients can participate in early 2020; MET alteration in KM-08 (Tepotinib), high tumor mutation burden in KM-12 (Ipilimumab and nivolumab). In conclusion, this project is efficient to detect actionable variations in mCRC. This novel knowledge provides an intriguing background to investigate new clinical trials with biomarker and give therapeutic opportunity for mCRC patients. By help of regulatory approval of innovative drugs and off-label use, biomarker-driven early phase clinical trials, it could be a huge therapeutic opportunity for refractory mCRC patients. (This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (Grant number: HI17C2206). Citation Format: Soohyeon Lee, Jae Sook Sung, Hee-Joon Chung, Yoon Ji Choi, Won Jin Chang, Ju Won Kim, Kyong Hwa Park, Yeul Hong Kim. Actionable genomic landscape of metastatic colorectal cancer patients in Korea: Interim data from K-MASTER project [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3620.

Abstract 23: Precision medicine approaches to Fanconi anemia oral cancer personalized prevention and treatment

Abstract There is an increased risk of oral cavity and other head and neck cancers as Fanconi patients live longer post transplantation. DNA repair defects in Fanconi patients contribute to “field effect” in this population, which causes frequent recurrences and often fatal, second primary oral malignancies. These developments show a need for translation of new basic science concepts for this patient population. We are examining the effects of both Metformin and Pioglitazone, and Polo kinase and Wee Kinase inhibitors in Fanconi anemia oral cancer cell lines, and leukoplakia control cells. We employed 3 FA oral cancer cell lines for the current study. We performed clonogenic and cell proliferation (MTT) experiments in replicates and repeated those experiments to establish initial dose responses of the inhibitors at biologically relevant concentrations. We used ANOVA analysis with a P<0.05 as our level of significance. Concurrently, we are examining pioglitazone-metformin signaling pathways in biopsies from precancerous oral lesion (non-FA) patients treated with pioglitazone in our multiple chemoprevention clinical trials via confocal fluorescence microscopy. We found both the Wee Kinase inhibitor and POLO kinase inhibitor resulted in dose dependent decreases in proliferation and clonogenic potential in several experiments in all cell lines. We observed decreased proliferation at 72 hours at clinically achievable serum levels of 75%. However, we also observed cytotoxic effects as well, as judged by MTT reading at 72 hours being lower than the original Day 0 MTT readings. Pioglitazone treatment also resulted in dose dependent decreases in cell proliferation and clonogenic potential at clinically achievable serum levels. Similar effects can be achieved with metformin, however, at higher doses. Additionally, we have identified surrogate endpoints as suitable pharmacodynamic readouts by IHC analysis of the cell lines. There are precision medicine treatments for FA-associated oral carcinoma and these are feasible, based on earlier promising results we present here. We are attempting to discover new treatment methodologies for these patients, as conventional agents and radiation therapy are often unacceptable, due to the DNA fragility of the patient population. In combination, these efforts support our future goals of chemoprevention in this underserved prevention population. Citation Format: Daniel K. Swenson, Beverly R. Wuertz, Mustafa M. Ali, Gretchen M. Unger, Frank G. Ondrey. Precision medicine approaches to Fanconi anemia oral cancer personalized prevention and treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 23.

Precision Medicine Treatments for Children With Leukemia

Precision Medicine Treatments for Children With Leukemia

Abstract B050: Identification of differentially expressed and spliced genes between breast, colon, lung, and prostate cancer from African American and white patients

Abstract Racial/ethnic disparity in cancer refers to the disproportionate incidence of and/or mortality from various cancers among population groups. In addition to differences in social, lifestyle and structural determinants of health, there is accumulating evidence for a biologic contribution to racial/ethnic disparity in cancer. To understand further the biologic mechanisms underlying racial/ethnic disparity in cancer, the analysis of differential aggregate gene expression and mutation among cancer patients of different population groups is important. Our recently published work reported differential RNA splicing as a critical mechanism underlying prostate cancer aggressiveness and drug response in African American (AA) patients. Here, we use R to analyze the Genomic Data Commons for differential aggregate gene expression (2-fold mean change, p < 0.001, Wilcoxon rank sum test) and TCGASpliceSeq to analyze TCGA for differential RNA splicing (20% median change, percent spliced in) between breast (BRCA, 183 AA and 761 white), colon (COAD, 56 AA and 194 white), squamous and adenocarcinoma lung (LUSC and LUAD, 34 and 57 AA and 392 and 444 white, respectively), and prostate (PRAD, 49 AA and 307 white) cancer specimens from AA and white patients. Our analysis identified 698 differentially expressed genes (DEGs) and 114 alternative RNA splicing events (ARSs) in BRCA, 107 DEGs and 57 ARSs in COAD, 25 and 117 DEGs and 115 and 53 ARSs in LUSC and LUAD, respectively, and 25 DEGs and 71 ARSs in PRAD from AA and white patients. Notably, comparing the lists of DEGs or ARSs from each cancer type with each of the other cancer types yields a minority of overlapping DEGs or ARSs among cancer types, indicating that race-related DEGs and ARSs are largely specific to cancer type. Pathway analysis of DEGs and ARSs reveals that the majority of these genes function in pathways relevant to cancer development and progression, such as programmed cell death, DNA repair, signal transduction, gene expression and metabolism. These analyses increase understanding of molecular mechanisms underlying racial/ethnic disparity in cancer. Upon further study of the function of these variants, such DEGs and ARSs have the potential to become candidates for development of new precision medicine interventions. Citation Format: Muthana Al Abo, Daniel J. George, Jennifer A. Freedman, Steven R. Patierno. Identification of differentially expressed and spliced genes between breast, colon, lung, and prostate cancer from African American and white patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B050.