DAVIS, CA, United States

Accelerated Medical Diagnostics, Llc

www.ACCELERATEDMEDDIAGNOSTICS.COM
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Stornetta A.,ETH Zurich | Zimmermann M.,University of California at Davis | Zimmermann M.,Accelerated Medical Diagnostics, Llc | Cimino G.D.,Accelerated Medical Diagnostics, Llc | And 3 more authors.
Chemical research in toxicology | Year: 2017

Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed. Aspects including measurement strategies, identification of adducts, and biological factors that influence the predictive relationship between DNA modification and biological response are addressed. A positive correlation between DNA adduct levels and response was observed for the majority of the studies, demonstrating the high potential of using DNA adducts from anticancer drugs as mechanism-based biomarkers of susceptibility, especially as bioanalysis approaches with higher sensitivity and throughput emerge.


Enright H.A.,Lawrence Livermore National Laboratory | Malfatti M.A.,Lawrence Livermore National Laboratory | Zimmermann M.,University of California at Davis | Zimmermann M.,Accelerated Medical Diagnostics, Llc | And 4 more authors.
Chemical Research in Toxicology | Year: 2016

Accelerator mass spectrometry (AMS) has been adopted as a powerful bioanalytical method for human studies in the areas of pharmacology and toxicology. The exquisite sensitivity (10-18 mol) of AMS has facilitated studies of toxins and drugs at environmentally and physiologically relevant concentrations in humans. Such studies include risk assessment of environmental toxicants, drug candidate selection, absolute bioavailability determination, and more recently, assessment of drug-target binding as a biomarker of response to chemotherapy. Combining AMS with complementary capabilities such as high performance liquid chromatography (HPLC) can maximize data within a single experiment and provide additional insight when assessing drugs and toxins, such as metabolic profiling. Recent advances in the AMS technology at Lawrence Livermore National Laboratory have allowed for direct coupling of AMS with complementary capabilities such as HPLC via a liquid sample moving wire interface, offering greater sensitivity compared to that of graphite-based analysis, therefore enabling the use of lower 14C and chemical doses, which are imperative for clinical testing. The aim of this review is to highlight the recent efforts in human studies using AMS, including technological advancements and discussion of the continued promise of AMS for innovative clinical based research. © 2016 American Chemical Society.


Cimino G.D.,Accelerated Medical Diagnostics, Llc | Pan C.-X.,University of California at Davis | Pan C.-X.,10535 Hospital Way | Henderson P.T.,Accelerated Medical Diagnostics, Llc | Henderson P.T.,University of California at Davis
Bioanalysis | Year: 2013

The personalized medicine revolution is occurring for cancer chemotherapy. Biomarkers are increasingly capable of distinguishing genotypic or phenotypic traits of individual tumors, and are being linked to the selection of treatment protocols. This review covers the molecular basis for biomarkers of response to targeted and cytotoxic lung and bladder cancer treatment with an emphasis on platinum-based chemotherapy. Platinum derivatives are a class of drugs commonly employed against solid tumors that kill cells by covalent attachment to DNA. Platinum-DNA adduct levels in patient tissues have been correlated to response and survival. The sensitivity and precision of adduct detection has increased to the point of enabling subtherapeutic dosing for diagnostics applications, termed diagnostic microdosing, prior to the initiation of full-dose therapy. The clinical status of this unique phenotypic marker for lung and bladder cancer applications is detailed along with discussion of future applications. © 2013 Future Science Ltd.


PubMed | Lawrence Livermore National Laboratory, Los Alamos National Laboratory, University of California at Davis and Accelerated Medical Diagnostics, Llc
Type: Journal Article | Journal: PloS one | Year: 2016

We report herein the development, functional and molecular characterization of an isogenic, paired bladder cancer cell culture model system for studying platinum drug resistance. The 5637 human bladder cancer cell line was cultured over ten months with stepwise increases in oxaliplatin concentration to generate a drug resistant 5637R sub cell line. The MTT assay was used to measure the cytotoxicity of several bladder cancer drugs. Liquid scintillation counting allowed quantification of cellular drug uptake and efflux of radiolabeled oxaliplatin and carboplatin. The impact of intracellular drug inactivation was assessed by chemical modulation of glutathione levels. Oxaliplatin- and carboplatin-DNA adduct formation and repair was measured using accelerator mass spectrometry. Resistance factors including apoptosis, growth factor signaling and others were assessed with RNAseq of both cell lines and included confirmation of selected transcripts by RT-PCR. Oxaliplatin, carboplatin, cisplatin and gemcitabine were significantly less cytotoxic to 5637R cells compared to the 5637 cells. In contrast, doxorubicin, methotrexate and vinblastine had no cell line dependent difference in cytotoxicity. Upon exposure to therapeutically relevant doses of oxaliplatin, 5637R cells had lower drug-DNA adduct levels than 5637 cells. This difference was partially accounted for by pre-DNA damage mechanisms such as drug uptake and intracellular inactivation by glutathione, as well as faster oxaliplatin-DNA adduct repair. In contrast, both cell lines had no significant differences in carboplatin cell uptake, efflux and drug-DNA adduct formation and repair, suggesting distinct resistance mechanisms for these two closely related drugs. The functional studies were augmented by RNAseq analysis, which demonstrated a significant change in expression of 83 transcripts, including 50 known genes and 22 novel transcripts. Most of the transcripts were not previously associated with bladder cancer chemoresistance. This model system and the associated phenotypic and genotypic data has the potential to identify some novel details of resistance mechanisms of clinical importance to bladder cancer.


PubMed | Lawrence Livermore National Laboratory, University of California at Davis and Accelerated Medical Diagnostics, Llc
Type: Journal Article | Journal: Chemical research in toxicology | Year: 2016

Gemcitabine metabolites cause the termination of DNA replication and induction of apoptosis. We determined whether subtherapeutic microdoses of gemcitabine are incorporated into DNA at levels that correlate to drug cytotoxicity. A pair of nearly isogenic bladder cancer cell lines differing in resistance to several chemotherapy drugs were treated with various concentrations of


PubMed | ETH Zurich, University of California at Davis and Accelerated Medical Diagnostics, Llc
Type: | Journal: Chemical research in toxicology | Year: 2016

Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed. Aspects including measurement strategies, identification of adducts, and biological factors that influence the predictive relationship between DNA modification and biological response are addressed. A positive correlation between DNA adduct levels and response was observed for the majority of the studies, demonstrating the high potential of using DNA adducts from anticancer drugs as mechanism-based biomarkers of susceptibility, especially as bioanalysis approaches with higher sensitivity and throughput emerge.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.50M | Year: 2012

We developed a technology called PlatinDx that, based upon preclinical data, can potentially identify chemoresistance in lung and bladder cancer patients before they receive carboplatin therapy. PlatinDx utilizes tracing of subtherapeutic microdoses of14C-labeled carboplatin with accelerator mass spectrometry (AMS), which has attomole (10-18 mole) sensitivity for 14C. We hypothesize that DNA damage caused by a single subtoxic microdose of carboplatin can predict patient outcomes such as tumor shrinkage, progression free survival and toxicity. The goal of the project is to test the clinical feasibility of PlatinDx in bladder and lung cancer patients. The PlatinDx data will be compared to ERCC1 expression using the Response Genetics RT-PCR assay as a benchmark. The resulting feasibility data will allow the design of a Pivotal Trial, which is required for FDA clearance and product launch.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 199.97K | Year: 2012

A. Background Information We developed a technology called PlatinDx that, based upon preclinical data, can potentially identify chemoresistance in breast cancer patients before they receive oxaliplatin therapy. PlatinDx utilizes tracing of subtherapeuticmicrodoses of 14C-labeled oxaliplatin with accelerator mass spectrometry (AMS), which has attomole (10-18 mole) sensitivity for 14C. We hypothesize that DNA damage caused by a single subtoxic microdose of oxaliplatin can predict patient outcomes suchas tumor shrinkage and survival. The goal of the project is to define the appropriate chemical (~1/100th the therapeutic dose) and radiochemical dose (a chest x-ray exposure) for the microdose composition, to establish protocols for the procedure and to gather preliminary clinical data. Breast cancer patients will receive a 14C-oxaliplatin microdose a few hours prior to normal biopsy. DNA will be isolated from white blood cells and left over tumor biopsy tissue. Drug-DNA damage levels will be measured by AMS and compared to outcomes such as tumor shrinkage, recurrence and severity of side effects. The data will be compared to ERCC1 expression and other biomarkers using the Response Genetics RT-PCR assay as a benchmark. The resulting feasibility data will allow the design of an SBIR Phase II diagnostics study. B. Phase I Technical Objectives The proposed Phase I clinical study will determine the feasibility of using [14C]oxaliplatin combined with AMS for clinical diagnostics trials using breast cancer patients. A clinical study is proposed due to substantial preclinical data (presented below). C. All patient recruitment for this SBIR Phase I study will be conducted by UC Davis. D. Experiments using accelerator mass spectrometry (AMS) will be performed by Accelerated Medical Diagnostics staff at the Lawrence Livermore National Laboratory.


Grant
Agency: European Commission | Branch: H2020 | Program: SME-1 | Phase: PHC-12-2014-1 | Award Amount: 71.43K | Year: 2015

Platinum-based chemotherapy is the primary therapeutic intervention for over 500,000 patients per year in the EU. Although some patients are cured by this type of chemotherapy, as many as 75% of lung cancer patients and 60% of bladder cancer patients show no benefit and could be more appropriately given alternative treatments, and therefore over 4bn annually is wasted on unnecessary treatments. There is a need for a rapid, accurate test to distinguish those patients who are likely to respond to chemotherapy and those who are not. Accelerated Medical Diagnostics aim to personalise chemotherapy for cancer patients through their own developed PlatinDx assay, which can be used to identify those patients which are appropriate for platinum-based chemotherapy. Cancer patients are given a microdose (1% of the therapeutic dose) of a platinum-based drug, followed by quantitation of drug-DNA adducts in biopsy tissye using accelerator mass spectrometry (AMS). Levels of drug-DNA damage are measured by AMS in white blood cells and tumor biopsy tissue, which are used as a predictor of therapeutic response. Within the innovation project Accelerated Medical Diagnoistics intend to: gain medical certification within the EU; run a scaled up clinical trial to gain significant results; and adress the EU market and launch their service in the EU.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 195.55K | Year: 2010

We developed a technology called PlatinDx that, based upon preclinical data, can potentially identify chemoresistance in cancer patients before they receive carboplatin or cisplatin therapy. PlatinDx utilizes tracing of subtherapeutic "microdoses" of 14C-labeled carboplatin with accelerator mass spectrometry (AMS), which has attomole (10-18 mole) sensitivity for 14C. We hypothesize that DNA damage caused by a single subtoxic microdose of carboplatin can predict patient outcomes such as tumor shrinkage and survival . The goal of the project is to define the appropriate chemical (-1 /1 DOth the therapeutic dose) and radiochemical (few percent of a chest x-ray exposure) microdose composition, to establish protocols for the procedure and to gather preliminary clinical data. Lung cancer patients will each receive a 14C-carboplatin microdose a few hours prior to normal biopsy. DNA will be isolated from white blood cells and left over tumor biopsy tissue. Drug-DNA damage levels will be measured by AMS and compared to outcomes such as tumor shrinkage, recurrence and severity of side effects. The data will be compared to ERCC1 expression and other biomarkers using the Response Genetics RT-PCR assay as a benchmark. The resulting feasibility data will allow the design of an SBIR Phase II pivotal diagnostic study.

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