Publications by authors named "Jamie E Medina"

9 Publications

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White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer.

Nat Commun 2020 Jan 27;11(1):525. Epub 2020 Jan 27.

Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.

Liquid biopsies are providing new opportunities for detection of residual disease in cell-free DNA (cfDNA) after surgery but may be confounded through identification of alterations arising from clonal hematopoiesis. Here, we identify circulating tumor-derived DNA (ctDNA) alterations through ultrasensitive targeted sequencing analyses of matched cfDNA and white blood cells from the same patient. We apply this approach to analyze samples from patients in the CRITICS trial, a phase III randomized controlled study of perioperative treatment in patients with operable gastric cancer. After filtering alterations from matched white blood cells, the presence of ctDNA predicts recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment. These analyses provide a facile method for distinguishing ctDNA from other cfDNA alterations and highlight the utility of ctDNA as a predictive biomarker of patient outcome to perioperative cancer therapy and surgical resection in patients with gastric cancer.
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http://dx.doi.org/10.1038/s41467-020-14310-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985115PMC
January 2020

Genome-wide cell-free DNA fragmentation in patients with cancer.

Nature 2019 06 29;570(7761):385-389. Epub 2019 May 29.

Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.
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http://dx.doi.org/10.1038/s41586-019-1272-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774252PMC
June 2019

Nanoformulation of Talazoparib Delays Tumor Progression and Ascites Formation in a Late Stage Cancer Model.

Front Oncol 2019 10;9:353. Epub 2019 May 10.

Department of Bioengineering, Northeastern University, Boston, MA, United States.

Talazoparib, a potent PARP inhibitor, induces synthetic lethality in -deficient cancers making it an attractive candidate for ovarian cancer treatment. However, its potency lends itself to side effects associated more closely with traditional chemotherapeutics than other clinically approved PARP inhbitors. We sought to formulate Talazoparib in a nanoparticle delivery system, which allows the drug to be administered intraperitoneally. This was done to specifically target peritoneal dissemination of late stage metastatic ovarian cancer and increase talazoparib's therapeutic efficacy while minimizing toxic side effects. NanoTalazoparib was developed and characterized with regard to its size, loading, and surface charge. Talazoparib and NanoTalazoparib were tested on a panel of murine and human cell lines and the dose response was compared to Olaparib's, the currently used PARP inhibitor. Therapeutic efficacy was tested in a peritoneal cancer model that mimics late stage disseminated disease. NanoTalazoparib has a diameter of about 70 nm with a neutral surface charge and ~75% encapsulation efficiency, which slowly releases the drug over several hours. Dose response analysis indicated that the murine cell lines with conditional , and deletions had the lowest IC50s. NanoTalazoparib administered on a schedule of three doses weekly slowed disease progression and resulted in significantly less mice with ascites at the end point compared to controls. These results indicate that the slow release nanoformulation, NanoTalazoparib, effectively delivers PARP inhibitor therapy to the peritoneal cavity for disseminated cancer treatment. The ability to decrease ascites formation with the introduction of intraperitoneal NanoTalazoparib suggests this treatment may be an effective way to treat ovarian cancer-associated ascites and slow disease progression.
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http://dx.doi.org/10.3389/fonc.2019.00353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524318PMC
May 2019

Early Noninvasive Detection of Response to Targeted Therapy in Non-Small Cell Lung Cancer.

Cancer Res 2019 03 20;79(6):1204-1213. Epub 2018 Dec 20.

Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, California.

With the advent of precision oncology, there is an urgent need to develop improved methods for rapidly detecting responses to targeted therapies. Here, we have developed an ultrasensitive measure of cell-free tumor load using targeted and whole-genome sequencing approaches to assess responses to tyrosine kinase inhibitors in patients with advanced lung cancer. Analyses of 28 patients treated with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders having nearly complete elimination of ctDNA (>98%). Molecular nonresponders displayed limited changes in ctDNA levels posttreatment and experienced significantly shorter progression-free survival (median 1.6 vs. 13.7 months, < 0.0001; HR = 66.6; 95% confidence interval, 13.0-341.7), which was detected on average 4 weeks earlier than CT imaging. ctDNA analyses of patients with radiographic stable or nonmeasurable disease improved prediction of clinical outcome compared with CT imaging. These analyses provide a rapid approach for evaluating therapeutic response to targeted therapies and have important implications for the management of patients with cancer and the development of new therapeutics. Cell-free tumor load provides a novel approach for evaluating longitudinal changes in ctDNA during systemic treatment with tyrosine kinase inhibitors and serves an unmet clinical need for real-time, noninvasive detection of tumor response to targeted therapies before radiographic assessment..
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481620PMC
March 2019

Unraveling the Cellular Mechanism of Assembling Cholesterols for Selective Cancer Cell Death.

Mol Cancer Res 2019 04 14;17(4):907-917. Epub 2018 Dec 14.

Department of Chemistry, Brandeis University, Waltham, Massachusetts.

Acquired drug resistance remains a challenge in chemotherapy. Here we show enzymatic, assembling of cholesterol derivatives to act as polypharmaceuticals for selectively inducing death of cancer cells via multiple pathways and without inducing acquired drug resistance. A conjugate of tyrosine and cholesterol (), formed by enzyme-catalyzed dephosphorylation of phosphorylate TC, self-assembles selectively on or in cancer cells. Acting as polypharmaceuticals, the assemblies of TC augment lipid rafts, aggregate extrinsic cell death receptors (e.g., DR5, CD95, or TRAILR), modulate the expression of oncoproteins (e.g., Src and Akt), disrupt the dynamics of cytoskeletons (e.g., actin filaments or microtubules), induce endoplasmic reticulum stress, and increase the production of reactive oxygen species, thus resulting in cell death and preventing acquired drug resistance. Moreover, the assemblies inhibit the growth of platinum-resistant ovarian cancer tumor in a murine model. This work illustrates the use of instructed assembly (iA) in cellular environment to form polypharmaceuticals that not only interact with multiple proteins, but also modulate membrane dynamics for developing novel anticancer therapeutics. IMPLICATIONS: As a multifaceted strategy for controlling cancer cell death, iA minimized acquired resistance of cancer cells, which is a new strategy to amplify the genetic difference between cancer and normal cells and provides a promise for overcoming drug resistance in cancer therapy. http://mcr.aacrjournals.org/content/molcanres/17/4/907/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445745PMC
April 2019

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer.

Clin Cancer Res 2018 03 20;24(6):1389-1401. Epub 2017 Dec 20.

Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy and , decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951622PMC
March 2018

Selectively Inducing Cancer Cell Death by Intracellular Enzyme-Instructed Self-Assembly (EISA) of Dipeptide Derivatives.

Adv Healthc Mater 2017 Aug 24;6(15). Epub 2017 Feb 24.

Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA, 02454, USA.

Tight ligand-receptor binding, paradoxically, is a major root of drug resistance in cancer chemotherapy. To address this problem, instead of using conventional inhibitors or ligands, this paper focuses on the development of a novel process-enzyme-instructed self-assembly (EISA)-to kill cancer cells selectively. Here it is demonstrated that EISA as an intracellular process to generate nanofibrils of short peptides for selectively inhibiting cancer cell proliferation, including drug resistant ones. As the process that turns the non-self-assembling precursors into the self-assembling peptides upon the catalysis of carboxylesterases (CES), EISA occurs intracellularly to selectively inhibit a range of cancer cells that exhibit relatively high CES activities. More importantly, EISA inhibits drug resistant cancer cells (e.g., triple negative breast cancer cells (HCC1937) and platinum-resistant ovarian cells (SKOV3, A2780cis)). With the IC values of 28-80 and 25-44 µg mL of l- and d-dipeptide precursors against cancer cells, respectively, EISA is innocuous to normal cells. Moreover, using coculture of cancer and normal cells, the selectivity of EISA is validated against cancer cells. Besides revealing that intracellular EISA cause apoptosis or necroptosis to kill the cancer cells, this work illustrates a new approach to amplify the enzymatic difference between cancer and normal cells and to expand the pool of drug candidates for potentially overcoming drug resistance in cancer therapy.
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http://dx.doi.org/10.1002/adhm.201601400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550337PMC
August 2017

Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.

PLoS One 2016 17;11(3):e0151089. Epub 2016 Mar 17.

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 02139.

The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05) (S2 Table). Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151089PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795743PMC
August 2016

Enzyme-Instructed Intracellular Molecular Self-Assembly to Boost Activity of Cisplatin against Drug-Resistant Ovarian Cancer Cells.

Angew Chem Int Ed Engl 2015 Nov 14;54(45):13307-11. Epub 2015 Sep 14.

Department of Chemistry, Brandeis University, 415 South St, Waltham, MA 02454 (USA).

Anticancer drug resistance demands innovative approaches that boost the activity of drugs against drug-resistant cancers without increasing the systemic toxicity. Here we show the use of enzyme-instructed self-assembly (EISA) to generate intracellular supramolecular assemblies that drastically boost the activity of cisplatin against drug-resistant ovarian cancer cells. We design and synthesize small peptide precursors as the substrates of carboxylesterase (CES). CES cleaves the ester bond pre-installed on the precursors to form the peptides that self-assemble in water to form nanofibers. At the optimal concentrations, the precursors themselves are innocuous to cells, but they double or triple the activity of cisplatin against the drug-resistant ovarian cancer cells. This work illustrates a simple, yet fundamental, new way to introduce non-cytotoxic components into combination therapies with cisplatin without increasing the systemic burden or side effects.
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http://dx.doi.org/10.1002/anie.201507157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681442PMC
November 2015
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