Cisplatin resistance and opportunities for precision medicine

Precision medicine, the customization of health care to an individual's genetic profile while accounting for biomarkers and lifestyle, has increasingly been adopted by health care stakeholders to guide the development of treatment options, improve treatment decision making, provide more patient-centered care, and better inform coverage and reimbursement decisions. Despite these benefits, key challenges prevent its broader use and adoption. On December 7-8, 2017, the Academy of Managed Care Pharmacy convened a group of stakeholders to discuss these challenges and provide recommendations to facilitate broader adoption and use of precision medicine across health care settings. These stakeholders represented the pharmaceutical industry, clinicians, patient advocacy, private payers, device manufacturers, health analytics, information technology, academia, and government agencies. Throughout the 2-day forum, participants discussed evidence requirements for precision medicine, including consistent ways to measure the utility and validity of precision medicine tests and therapies, limitations of traditional clinical trial designs, and limitations of value assessment framework methods. They also highlighted the challenges with evidence collection and data silos in precision medicine. Interoperability within and across health systems is hindering clinical advancements. Current medical coding systems also cannot account for the heterogeneity of many diseases, preventing health systems from having a complete understanding of their patient population to inform resource allocation. Challenges faced by payers, such as evidence limitations, to inform coverage and reimbursement decisions in precision medicine, as well as legal and regulatory barriers that inhibit more widespread data sharing, were also identified. While a broad range of perspectives was shared throughout the forum, participants reached consensus across 2 overarching areas. First, there is a greater need for common definitions, thresholds, and standards to guide evidence generation in precision medicine. Second, current information silos are preventing the sharing of valuable data. Collaboration among stakeholders is needed to support better information sharing, awareness, and education of precision medicine for patients. The recommendations brought forward by this diverse group of experts provide a set of solutions to spur widespread use and application of precision medicine. Taken together, successful adoption and use of precision medicine will require input and collaboration from all sectors of health care, especially patients. DISCLOSURES This AMCP Partnership Forum and the development of the proceedings document were supported by Amgen, Foundation Medicine, Genentech, Gilead, MedImpact, National Pharmaceutical Council, Precision for Value, Sanofi, Takeda, and Xcenda.

Precision medicine, the customization of health care to an individual's genetic profile while accounting for biomarkers and lifestyle, has increasingly been adopted by health care stakeholders to guide the development of treatment options, improve treatment decision making, provide more patient-centered care, and better inform coverage and reimbursement decisions. Despite these benefits, key challenges prevent its broader use and adoption. On December 7-8, 2017, the Academy of Managed Care Pharmacy convened a group of stakeholders to discuss these challenges and provide recommendations to facilitate broader adoption and use of precision medicine across health care settings. These stakeholders represented the pharmaceutical industry, clinicians, patient advocacy, private payers, device manufacturers, health analytics, information technology, academia, and government agencies. Throughout the 2-day forum, participants discussed evidence requirements for precision medicine, including consistent ways to measure the utility and validity of precision medicine tests and therapies, limitations of traditional clinical trial designs, and limitations of value assessment framework methods. They also highlighted the challenges with evidence collection and data silos in precision medicine. Interoperability within and across health systems is hindering clinical advancements. Current medical coding systems also cannot account for the heterogeneity of many diseases, preventing health systems from having a complete understanding of their patient population to inform resource allocation. Challenges faced by payers, such as evidence limitations, to inform coverage and reimbursement decisions in precision medicine, as well as legal and regulatory barriers that inhibit more widespread data sharing, were also identified. While a broad range of perspectives was shared throughout the forum, participants reached consensus across 2 overarching areas. First, there is a greater need for common definitions, thresholds, and standards to guide evidence generation in precision medicine. Second, current information silos are preventing the sharing of valuable data. Collaboration among stakeholders is needed to support better information sharing, awareness, and education of precision medicine for patients. The recommendations brought forward by this diverse group of experts provide a set of solutions to spur widespread use and application of precision medicine. Taken together, successful adoption and use of precision medicine will require input and collaboration from all sectors of health care, especially patients. DISCLOSURES This AMCP Partnership Forum and the development of the proceedings document were supported by Amgen, Foundation Medicine, Genentech, Gilead, MedImpact, National Pharmaceutical Council, Precision for Value, Sanofi, Takeda, and Xcenda.

Precision medicine - individualizing care for patients and addressing variations in treatment response - is likely to be important in improving the nation's health in a cost-effective manner. Despite this promise, widespread use of precision medicine, specifically genomic markers, in clinical care has been limited in practice to date. Lack of evidence, clear evidence thresholds, and reimbursement have been cited as major barriers. Health economics frameworks and tools can elucidate the effects of legal, regulatory, and reimbursement policies on the use of precision medicine while guiding research investments to enhance the appropriate use of precision medicine. Despite the capacity of economics to enhance the clinical and human impact of precision medicine, application of health economics to precision medicine has been limited - in part because precision medicine is a relatively new field - but also because precision medicine is complex, both in terms of its applications and implications throughout medicine and the healthcare system. The goals of this review are several-fold: (1) provide an overview of precision medicine and key policy challenges for the field; (2) explain the potential utility of economics methods in addressing these challenges; (3) describe recent research activities; and (4) summarize opportunities for cross-disciplinary research.

Cisplatin is among the most widely used broadly active cytotoxic anticancer drugs; however, its clinical efficacy is often limited by primary or the development of secondary resistance. Several mechanisms have been implicated in cisplatin resistance, including reduced drug uptake, increased cellular thiol/folate levels and increased DNA repair. More recently, additional pathways have been characterized indicating that altered expression of oncogenes that subsequently limit the formation of cisplatin-DNA adducts and activate anti-apoptotic pathways may also contribute to the resistance phenotype. Several lines of evidence suggest that expression of ras oncogenes can confer resistance to cisplatin by reducing drug uptake and increasing DNA repair; however, this is not a uniform finding. Tumor cells, in contrast to normal cells, respond to cisplatin exposure with transient gene expression to protect or repair their chromosomes. The c-fos/AP-1 complex, a master switch for turning on other genes in response to DNA-damaging agents, has been shown to play a major role in cisplatin resistance. In addition, AP-2 transcription factors, modulated by protein kinase A, are also implicated in cisplatin resistance by regulating genes encoding for DNA polymerase beta and metallothionines. Furthermore, considerable evidence indicates that mutated p53 plays a significant role in the development of cisplatin resistance since several genes implicated in drug resistance and apoptosis (e.g. mismatch repair, bcl-2, high mobility group proteins, DNA polymerases alpha and beta, PCNA, and insulin-like growth factor) are known to be regulated by the p53 oncoprotein. Improved understanding of molecular factors for the development of cisplatin resistance may allow the prediction of clinical response to cisplatin-based treatment. Furthermore, the identification of oncogenes involved in cisplatin resistance has already led to in vitro approaches which successfully inactivated these genes using ribozymes or antisense oligodeoxynucleotides, thus restoring cisplatin sensitivity. It is conceivable that these strategies, once transferred to a clinical setting, may have the potential to enhance the efficacy of cisplatin against a great variety of malignancies and thus more fully exploit the antineoplastic and curative potential of this drug.

Targeting STAT3 inhibition to reverse cisplatin resistance

Purpose of review: Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease (CKD) for which many treatments exist that have been shown to prevent CKD progression and kidney failure. However, DKD is a complex and heterogeneous etiology of CKD with a spectrum of phenotypes and disease trajectories. In this narrative review, we discuss precision medicine approaches to DKD, including genomics, metabolomics, proteomics, and their potential role in the management of diabetes mellitus and DKD. A patient and caregivers of patients with lived experience with CKD were involved in this review. Sources of information: Original research articles were identified from MEDLINE and Google Scholar using the search terms “diabetes,” “diabetic kidney disease,” “diabetic nephropathy,” “chronic kidney disease,” “kidney failure,” “dialysis,” “nephrology,” “genomics,” “metabolomics,” and “proteomics.” Methods: A focused review and critical appraisal of existing literature regarding the precision medicine approaches to the diagnosis, prognosis, and treatment of diabetes and DKD framed by a patient partner’s/caregiver’s lived experience. Key findings: Distinguishing diabetic nephropathy from CKD due to other types of DKD and non-DKD is challenging and typically requires a kidney biopsy for a diagnosis. Biomarkers have been identified to assist with the prediction of the onset and progression of DKD, but they have yet to be incorporated and evaluated relative to clinical standard of care CKD and kidney failure risk prediction tools. Genomics has identified multiple causal genetic variants for neonatal diabetes mellitus and monogenic diabetes of the young that can be used for diagnostic purposes and to specify antiglycemic therapy. Genome-wide-associated studies have identified genes implicated in DKD pathophysiology in the setting of type 1 and 2 diabetes but their translational benefits are lagging beyond polygenetic risk scores. Metabolomics and proteomics have been shown to improve diagnostic accuracy in DKD, have been used to identify novel pathways involved in DKD pathogenesis, and can be used to improve the prediction of CKD progression and kidney failure as well as predict response to DKD therapy. Limitations: There are a limited number of large, high-quality prospective observational studies and no randomized controlled trials that support the use of precision medicine based approaches to improve clinical outcomes in adults with or at risk of diabetes and DKD. It is unclear which patients may benefit from the clinical use of genomics, metabolomics and proteomics along the spectrum of DKD trajectory. Implications: Additional research is needed to evaluate the role of the use of precision medicine for DKD management, including diagnosis, differentiation of diabetic nephropathy from other etiologies of DKD and CKD, short-term and long-term risk prognostication kidney outcomes, and the prediction of response to and safety of disease-modifying therapies.

Cisplatin is one of the most widely used cytotoxic anticancer drugs for the treatment of solid malignancies, including lung, testicular, ovarian, head and neck, colorectal, bladder cancers, etc. However, its clinical efficacy is often limited by the development of chemoresistance. Several mechanisms have been implicated in cisplatin resistance, such as reduced drug uptake, increased cellular thiol/folate levels and increased DNA repair. Celastrol, a quinone methide triterpene, is an active compenent of the traditional Chinese medicinal plant Tripterygium Wilfordii, which exhibits significant antitumor activity in different cancer models in vitro and in vivo. In this study, we sought to determine the effect of celastrol on cisplatin resistance cancer cells and the possible involved molecular mechanism. Our data show that celastrol had similar cytotoxic effects on both A549 parental and A549/DDP cisplatin resistant cells. The IC50 values of celastrol to both cell lines are at the concentration of μM range. Celastrol also induced cell apoptosis with ROS accumulation, loss of mitochondrial membrane potentials, cleavage of PARP and caspases in a dose- and time-dependent manner in both cell lines. These findings might provide significant strategy for overcoming cisplatin resistance in clinic, and define the novel mechanism of celastrol-induced anticancer activity. Citation Format: Zhi Shi. Overcoming cisplatin resistance by celastrol in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2245. doi:10.1158/1538-7445.AM2013-2245 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

In recent years, the potential use of digital twins (DTs) in healthcare sectors is becoming a growing research area that can lead to more individualized patient care. In this regard the use of precision medicine towards personalized treatment is emerging as promising approach that takes into account of individual variability in genes, environment and lifestyle of each person. Moreover, precision medicine provides a framework for designing a targeted treatment for individual patients by combining clinical and demographic information as well as biomarkers and medical imaging data. The process of diagnosing and treating patients, particularly in the context of cancer treatment, involves multiple steps and can also have certain limitations. Introducing DTs in personalized treatment planning, including the use of precision medicine, could support and enhance the cancer care. Although the digital twin model has the potential to accurately diagnose cancer, advanced monitoring systems are necessary for commercial use.

Background: Patient-derived xenografts (PDX) as xenotransplantation of human tumors into athymic nude mice have become the hallmark of preclinical modelling in cancer research. They are particularly useful in the characterization of targeted therapies in drug development. We sough to build a collection of PDX connected to our early phase trials facility for preclinical testing of new drugs. Methods: Between March 2017 and October 2019, a total of 483 samples from patients with cancer were obtained for implant. A full review of the characteristics including histological particularities, molecular findings and treatment experience was reviewed for a full description of the collection. Results: 483 tumor samples were implanted. A total of 157 achieved tumor growth (defined as a target volume of 150 mm3 in at least three consecutive measurements). Here, we present the description of 121 successfully engrafted models passed at least 2 times from initial implant. Most common type of cancer is colorectal adenocarcinoma (CRC=63; 52%) (MSI-H=8, 13%). 20 are molecularly characterized: KRAS: 9 (45%); NRAS=1 (5%) and BRAF=4 (20%). Prior therapy: chemo=16, VEGFi=9, EGFRi=1, ICi=1. Fifteen ovarian carcinomas (12,39%). Three BRCA2m (2) and EPCAMm (1). Eight breast carcinomas (6,6%): 6 Invasive Ductal Carcinomas (IDC) (three are triple negative with BRCA2m; 3 resistant to aromatase inhibitors, and 1 to a CDK inhibitor), 1 papillary carcinoma and 1 medullary carcinoma harboring a TP53 mutation. Eleven non-small cell lung cancers grew successfully, all EGFRwt (KRASm=2). One squamous cell carcinoma with a BRD4/NUTM1 fusion treated with cisplatin/vinorelbine and atezolizumab prior to implant. Eight glioblastomas (prior temozolomide=3 (37%), MGMTmt=5 (62%) and IDHm=1 (12%). One uveal melanoma with a MET fusion. The collection also includes endometrial MSI-H cancers (2), bladder (2), head and neck (1), kidney (4), pancreas (2), biliary tract (1) and cervix carcinomas (1) and one osteosarcoma. Conclusions: The importance of PDX development programs relies on the reproducibility of tumors with specific oncogenic drivers potentially targetable. A full comprehensive characterization of PDX shareable collections are paramount for tracking of molecular, diagnostic, prognostic and predictive markers of drug response. Citation Format: Natalia Baños, Tatiana Hernandez-Guerrero, Victoria Bonilla, Bernard Doger, Laura Del Puerto, Emily Robb, Cecilio Cadena, Jesus Garcia-Foncillas, Victor Moreno, Michael Wick. Establishment of a comprehensive patient derived xenograft (PDX) collection for use in precision medicine; A project from START Madrid- FJD [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 5061.

Introduction: Cisplatin is used as a standard chemotherapeutic agent for head and neck cancer treatment. However, some head and neck cancers have cisplatin resistance, leading to difficulty in treatment and poor prognosis. Overcoming cisplatin resistance remains an important strategy to improve prognoses for head and neck cancer patients.Objective: Elucidation of the mechanisms underlying cisplatin resistance can suggest novel targets to enhance the anticancer effects of cisplatin for treating head and neck cancers.Material and methods: We used a cisplatin-resistant human maxillary cancer cell line, IMC-3CR to analyse the cisplatin resistance mechanisms. Cisplatin-induced genes were analysed in IMC-3CR cells using PCR array. Among the genes with expression increased by cisplatin, we specifically examined SESN1. SESN family reportedly regenerates peroxiredoxin and suppresses oxidative DNA injury by reactive oxygen species (ROS), which can be induced by chemotherapeutic agents such as cisplatin, radiation, and hyperthermia. The function of SESN1 in cisplatin resistance and ROS generation were analysed using specific RNAi.Results: Results show that SESN1 was induced by cisplatin treatment in IMC-3CR cells. Suppression of SESN1 by RNAi induced apoptosis and reduced cell viability through enhancement of ROS after cisplatin treatment. Moreover, suppression of SESN1 enhanced the cell-killing effects of hyperthermia with increased ROS, but did not affect the cell-killing effects of radiation.Conclusions: This study demonstrated the participation of SESN1 in cisplatin and hyperthermia resistance of human head and neck cancers. SESN1 is a novel molecular target to overcome cisplatin resistance and hyperthermia resistance and improve head and neck cancer treatment.

Histone modification is important for maintaining chromatin structure and function. Recently, histone acetylation has been shown to have a critical regulatory role in both transcription and DNA repair. We report here that expression of histone acetyltransferase (HAT) genes is associated with cisplatin resistance. We found that Tip60 is overexpressed in cisplatin-resistant cells. The expression of two other HAT genes, HAT1 and MYST1, did not differ between drug-sensitive and -resistant cells. Knockdown of Tip60 expression rendered cells sensitive to cisplatin but not to oxaliplatin, vincristine, and etoposide. Tip60 expression is significantly correlated with cisplatin sensitivity in human lung cancer cell lines. Interestingly, the promoter region of the Tip60 gene contains several E boxes, and its expression was regulated by the E-box binding circadian transcription factor Clock but not by other E-box binding transcription factors such as c-Myc, Twist, and USF1. Hyperacetylation of H3K14 and H4K16 was found in cisplatin-resistant cells. The microarray study reveals that several genes for DNA repair are down-regulated by the knockdown of Tip60 expression. Our data show that HAT gene expression is required for cisplatin resistance and suggest that Clock and Tip60 regulate not only transcription, but also DNA repair, through periodic histone acetylation.

Background/Objectives: Lung cancer ranks as the leading cause of cancer-related deaths globally and is highly associated with cisplatin resistance due to both intrinsic and extrinsic mechanisms. Proliferating Cell Nuclear Antigen (PCNA) plays a critical role in molecular processes, such as DNA replication and repair, chromatin structure maintenance, and cell cycle progression. PCNA is known as a molecular marker for proliferation and an excellent inhibition target to shut down highly proliferative cells. One of the mechanisms of cisplatin resistance is the increase in DNA repair, and studies have reported an association between PCNA, lung cancer, and cisplatin treatment. The present study aimed to characterize the absence of PCNA in A549 lung adenocarcinoma cells. Methods: Employing a CRISPR/Cas9 gene-editing approach, we generated a monoclonal cell culture, termed PKO (PCNA knockout). Results: PKO cells exhibited a residual PCNA expression, significantly decreased clonogenic potential and ubiquitylation at K164 residue. IC50 assay suggested that PKO cells could not acquire cisplatin resistance when compared to PX. After cisplatin treatment, PKO cells presented impaired ubiquitylation and did not have increased STAT3 phosphorylation (Tyr705), a previously characterized mechanism of cisplatin resistance. Conclusions: We suggest that PCNA participates in cisplatin resistance in A549, partially by DNA damage tolerance through failure on PCNA monoubiquitylation, and its inhibition may be an approach to circumvent cisplatin resistance.

Platinum-based antineoplastic drugs are chemotherapeutic agents to usually treat gastric cancer (GC) include cisplatin. However, the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Especially, increased DNA repair is drug targetable mechanism and useful in the treatment strategy of cisplatin-resistant cancer. Casein kinase 2 (CK2) has critical role of multiple cellular processes with DNA repair. For this reason, research for CK2 expression correlated with DNA repair mechanism is important in gastric cancer. Combination of cisplatin and CK2 inhibitor (CX-4945, also known as Silmitasertib, Senhwa Biosciences, USA) may improve cisplatin-induced DNA damage for GC treatment. In this study, we screened sensitivity of cisplatin and CX-4945 in 49 GC cell lines by MTT assay. For molecular profiling, we analyzed variants and gene expression using whole exome sequencing and RNA sequencing. RNA and protein expression of CK2 subunits (α/α’) using real-time RT-PCR and Western blot. Also, activity of CK2α was measured by ELISA. Combination treatment performed different schedules including concurrent and sequential. Synergistic effect was analyzed by Bliss Independence model. As CK2 profiling, CK2α’ mRNA expression was a tendency to correlated with CX-4945 sensitivity(p=0.0504). Moreover, CK2α’ protein expression was a correlated with CX-4945 sensitivity(p=0.0252). Other molecular profiling did not reveal any clear correlations. Twenty one (Group1: cisplatin extremely resistant and CK2 high, Group2: cisplatin intermediate resistant regardless of CK2 expression) cell lines were performed combination treatment. Both YCC-21 and YCC-28 cell lines show synergistic effect (+20% and +22%, respectively) in concurrent schedule. Only MKN-74 cell line show synergistic effect (+11%) in Pre-addition. The 4 cell lines (YCC-18, YCC-38, SNU-1 and -216) were show synergistic effect (+10%, +37%, +11% and +19%, respectively) in Post-addition. In conclusion, early inhibition of CK2 shows synergistic effect in group 1, because CK2 is high expression. In group 2, late inhibition of CK2 demonstrated synergistic effect. It means CK2-related DNA repair is up-regulating for repair to cisplatin-induced DNA damage. Personalized the treatment schedule for inhibit CK2-induced DNA repair is a new strategy to restore cisplatin resistant in GC. Citation Format: Hyun Myong Kim, Inhye Jeong, Kyu Hyun Park, Tae Soo Kim, Woo Sun Kwon, Hei-Cheul Jeung, Minkyu Jung, Sun Young Rha. Overcoming cisplatin resistance through the combination treatment with CK2 inhibitor, CX-4945, in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1216. doi:10.1158/1538-7445.AM2017-1216

Cancer is one of the leading causes of mortality worldwide. As the population increases, there is an enriched thrust for screening a newer delivery system for anticancer agents to treat cancer. Therefore, exosome-mediated cell communication is the hallmark of its participation in cancer metastasis and progression. Furthermore, the inward budding of endosomes is referred to as the multivesicular body. Exosome constitutes phospholipid bilayer-bound vesicles. It transfers bioactive compounds between various cells and the tumor microenvironment. In addition, they were selectively loading oncogenic molecules into exosomes for drug delivery. Exosome act as a potential biomarker in detecting therapeutic targets. Furthermore, exosomes fused with the cell membrane and were used as a diagnostic tool for cancer therapy. Exosomes are used in several ways to inhibit cancer cell growth. It can also carry genetic information and anticancer medications, preventing tumor cells from releasing exosomes. In addition, exosome-based drug delivery is utilized for preclinical and clinical trials, promoting the development of newer anticancer agents that suppress cancer growth. Exosomes further improve the immune system and help to generate new blood vessels. It blocks apoptosis and prevents cancer resistance. Exosomes act as cargo, allowing them to load proteins, chemotherapeutics, RNAs, DNAs, and hydrophobic drugs. Exosomes help to achieve advancement in cancer management through the use of precision medicine. The current review highlighted significant aspects of exosomes for cancer mechanism and prevention. Furthermore, novel strategies aimed to promote the clinical application of exosomes in cancer diagnosis and therapeutic impact. Finally, this review plays a pivotal role for the researchers in the industry and academics working in this field.

Proteasome Inhibitor PS-341 Induces Apoptosis in Cisplatin-resistant Squamous Cell Carcinoma Cells by Induction of Noxa