Publications by authors named "Andrea Wong"

111 Publications

Extracellular vesicles, the cornerstone of next-generation cancer diagnosis?

Semin Cancer Biol 2021 May 11. Epub 2021 May 11.

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore 119228, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Cancer has risen up to be a major cause of mortality worldwide over the past decades. Despite advancements in cancer screening and diagnostics, a significant number of cancers are still diagnosed at a late stage with poor prognosis. Hence, the discovery of reliable and accurate methods to diagnose cancer early would be of great help in reducing cancer mortality. Extracellular vesicles (EVs) are phospholipid vesicles found in many biofluids and are released by almost all types of cells. In recent years, using EVs as cancer biomarkers has garnered attention as a novel technique of cancer diagnosis. Compared with traditional tissue biopsy, there are many advantages that this novel diagnostic tool presents - it is less invasive, detects early-stage asymptomatic cancers, and allows for monitoring of tumour progression. As such, EV biomarkers have great potential in improving the diagnostic accuracy of cancers and guiding subsequent therapeutic decisions. Efficient isolation and accurate characterization of EVs are essential for reliable outcomes of clinical application. However, these are complicated by the size and biomolecular diversity of EVs. In this review, we present an analysis and evaluation of the current techniques of EV isolation and characterization, as well as discuss the potential EV biomarkers for specific types of cancer. Taken together, EV biomarkers have a lot of potential as a novel method in cancer diagnostics and diagnosis. However, more work is still needed to streamline the purification, characterization and biomarker identification process to ensure optimal outcomes for patients.
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http://dx.doi.org/10.1016/j.semcancer.2021.05.011DOI Listing
May 2021

Facilitators and barriers to medication adherence with adjuvant endocrine therapy in women with breast cancer: a structural equation modelling approach.

Breast Cancer Res Treat 2021 May 4. Epub 2021 May 4.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, 12 Science Drive 2, #10-03F, Singapore, 117549, Singapore.

Purpose: To identify a structure to explain the relationship between socio-clinico factors, necessity-concerns beliefs, and perceived barriers to adherence with adjuvant endocrine therapy (AET) amongst women with breast cancer.

Methods: Participants were 244 patients with early-stage breast cancer recruited from two tertiary hospitals from May 2015 to December 2018 who completed questionnaires on medication adherence (Simplified Medication Adherence Questionnaire), necessity-concerns beliefs (Beliefs about Medicine Questionnaire), and barriers to adherence (Adherence Starts with Knowledge Questionnaire). Socio-clinico variables were collected via interview and medical records review. Structural equation modelling was applied to examine the relationships between these variables and possible mediating effects of necessity-concerns beliefs on adherence to AET.

Results: The median age of the study participants was 61 (range 32-80) years and the median duration on AET was 1.6 (IQR 1.2-2.6) years. Adherence was positively associated with age (β = 0.145, 95% CI: 0.011 to 0.279, p = 0.034) and negatively associated with barriers (β = - 0.381, 95% CI: - 0.511 to - 0.251, p < 0.001). There was no effect of Necessity (β = 0.006, 95% CI: - 0.145 to 0.158, p = 0.933) or Concerns (β = 0.041, 95% CI: - 0.117 to 0.199, p = 0.614) on adherence. Necessity-concerns beliefs were also not significant mediators in the relationship between socio-clinico factors and medication adherence.

Conclusions: Older age and lower barriers to adherence were associated with higher adherence scores. Necessity-concerns beliefs did not have a significant effect on adherence as majority of the patients identified forgetfulness as a reason for non-adherence.
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http://dx.doi.org/10.1007/s10549-021-06204-9DOI Listing
May 2021

Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer.

NPJ Breast Cancer 2021 Apr 16;7(1):44. Epub 2021 Apr 16.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co-mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.
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http://dx.doi.org/10.1038/s41523-021-00251-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052445PMC
April 2021

Microbial memories.

Immunity 2021 Feb;54(2):201-204

Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Electronic address:

The microbiota impedes pathogen invasion of the intestinal ecosystem, a phenomenon termed colonization resistance. In an upcoming issue of Cell, Stacy et al. describe host-initiated metabolite pathways that functionally alter the microbiota after primary infection, thereby augmenting colonization resistance to subsequent infection.
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http://dx.doi.org/10.1016/j.immuni.2021.01.009DOI Listing
February 2021

Beliefs about medicines and adherence in women with breast cancer on adjuvant endocrine therapy.

J Health Psychol 2021 Feb 7:1359105321990776. Epub 2021 Feb 7.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.

The Beliefs about Medicines Questionnaire (BMQ) and Adherence Starts with Knowledge (ASK-12) questionnaire were originally developed and validated in Western populations to assess beliefs and barriers to medication adherence. The study aim is to validate the BMQ and ASK-12 questionnaire for use in a Singapore population with early stage breast cancer. English-speaking women on adjuvant endocrine therapy ( = 157) were recruited. The BMQ-Specific showed good internal consistency with structural validity. The internal consistency of BMQ-General and ASK-12 Behaviour scale improved with the new factor structure obtained from exploratory factor analysis. Further studies are needed to confirm these factor structures.
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http://dx.doi.org/10.1177/1359105321990776DOI Listing
February 2021

Tiny miRNAs Play a Big Role in the Treatment of Breast Cancer Metastasis.

Cancers (Basel) 2021 Jan 18;13(2). Epub 2021 Jan 18.

Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.

Distant organ metastases accounts for the majority of breast cancer deaths. Given the prevalence of breast cancer in women, it is imperative to understand the underlying mechanisms of its metastatic progression and identify potential targets for therapy. Since their discovery in 1993, microRNAs (miRNAs) have emerged as important regulators of tumour progression and metastasis in various cancers, playing either oncogenic or tumour suppressor roles. In the following review, we discuss the roles of miRNAs that potentiate four key areas of breast cancer metastasis-angiogenesis, epithelial-mesenchymal transition, the Warburg effect and the tumour microenvironment. We then evaluate the recent developments in miRNA-based therapies in breast cancer, which have shown substantial promise in controlling tumour progression and metastasis. Yet, certain challenges must be overcome before these strategies can be implemented in clinical trials.
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http://dx.doi.org/10.3390/cancers13020337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831489PMC
January 2021

EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy.

Nat Commun 2020 11 18;11(1):5878. Epub 2020 Nov 18.

Cancer Precision Medicine, Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis, Singapore, 138672, Singapore.

HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors.
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http://dx.doi.org/10.1038/s41467-020-19704-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674491PMC
November 2020

Targeting Hypoxia-Inducible Factor-1-Mediated Metastasis for Cancer Therapy.

Antioxid Redox Signal 2021 Jun 25;34(18):1484-1497. Epub 2021 Jan 25.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Hypoxia is emerging as a crucial regulator of the tumor microenvironment; it governs the metastatic potential of multiple primary cancers. It is also potentially involved in the regulation of tumorigenesis, tumor metabolism, and proangiogenic activity. A wealth of clinical data across a wide range of cancer types has revealed strong correlations between hypoxia or the overexpression of hypoxia-inducible transcription factors and the rates of distant metastases and poor prognoses. Hypoxia-inducible factor (HIF)-1α, one of the key regulatory molecules of the HIF-1 signaling pathways, is involved in multiple crucial steps in the metastatic cascade. Here, we present recent findings on the roles of the HIF-1 complex in tumor metastasis and highlight the potential of HIF-1α as a target for abrogating tumor metastasis. Moreover, we systematically describe the regulatory role of HIF-1 at each step of the metastatic cascade. Finally, we present the most recent advances in potential pharmacological interventions and the development of specific HIF-1 inhibitors for blocking tumor metastasis. Well-designed clinical trials are urgently needed to validate the anti-metastatic activity of HIF-1 inhibitors discovered in preclinical models. . 34, 1484-1497.
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http://dx.doi.org/10.1089/ars.2019.7935DOI Listing
June 2021

Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy.

Molecules 2020 Oct 20;25(20). Epub 2020 Oct 20.

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.

Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.
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http://dx.doi.org/10.3390/molecules25204831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588013PMC
October 2020

Integration of Antiangiogenic Therapy with Cisplatin and Gemcitabine Chemotherapy in Patients with Nasopharyngeal Carcinoma.

Clin Cancer Res 2020 10 14;26(20):5320-5328. Epub 2020 Aug 14.

Department of Haematology-Oncology, National University Cancer Institute, Singapore.

Purpose: Induction cisplatin and gemcitabine chemotherapy is a standard treatment for locally advanced nasopharyngeal carcinoma (NPC). Inhibition of VEGF axis has been shown to promote maturation of microvasculature and improve perfusion. We conducted a four-arm study to assess the effect of two doses of either sunitinib or bevacizumab with chemotherapy in NPC.

Patients And Methods: Patients with treatment-naïve locally advanced NPC were treated with three cycles of 3-weekly cisplatin and gemcitabine preceded by 1 week of anti-VEGF therapy for each cycle, followed by standard concurrent chemoradiation: arm A patients received 7 days of 12.5 mg/day sunitinib; arm B 7 days of 25 mg/day sunitinib; arm C bevacizumab 7.5 mg/kg infusion; arm D bevacizumab 2.5 mg/kg infusion. Patients with metastatic NPC were treated with up to six cycles of similar treatment without concurrent chemoradiation.

Results: Complete metabolic response (mCR) by whole body FDG PET was highest in arm C (significant difference in four groups Fisher exact test = 0.001; type 1 error = 0.05), with 42% mCR (95% confidence interval, 18-67) and 3-year relapse-free survival of 88% in patients with locally advanced NPC. Significant increase in pericyte coverage signifying microvascular maturation and increased immune cell infiltration was observed in posttreatment tumor biopsies in Arm C. Myelosuppression was more profound in sunitinib containing arms, and tolerability was established in arm C where hypertension was the most significant toxicity.

Conclusions: Bevacizumab 7.5 mg/kg with cisplatin and gemcitabine was well tolerated. Promising tumor response was observed and supported mechanistically by positive effects on tumor perfusion and immune cell trafficking into the tumor.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1727DOI Listing
October 2020

Improving medication adherence with adjuvant aromatase inhibitor in women with breast cancer: A randomised controlled trial to evaluate the effect of short message service (SMS) reminder.

Breast 2020 Oct 2;53:77-84. Epub 2020 Jul 2.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, 12 Science Drive 2, #10-03F, 117549, Singapore; Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, 1E Kent Ridge Road, 119228, Singapore. Electronic address:

Background: Medication adherence is crucial for improving clinical outcomes in the treatment of patients. We evaluate the effect of short message service (SMS) reminder on medication adherence and serum hormones in patients with breast cancer on aromatase inhibitors.

Methods: An open-label, multi-centre, prospective randomised controlled trial of SMS versus Standard Care was conducted. Medication adherence was assessed via self-report using the Simplified Medication Adherence Questionnaire at baseline, 6 month, and 1 year. Androstenedione, estradiol, and estrone were measured at baseline and 1 year. The χ test and mixed effects logistic regression was performed to compare medication adherence between groups. Difference in androstenedione and estrone levels were assessed using analysis of covariance, whereas χ test and logistic regression was used for estradiol. Analysis was based on intention-to-treat.

Results: A total of 244 patients were randomised to receive weekly SMS reminder (n = 123) or Standard Care (n = 121) between May 2015 and December 2018. The odds of adherence was higher at 6-month in SMS (OR = 1.78, 95% CI 1.04-3.05, p = 0.034), and not significantly different at 1-year (OR = 1.15, 95% CI: 0.67-1.96 p = 0.617). Mixed effects logistic regression analysis showed higher odds of adherence in SMS over the 1-year period (OR = 2.35, 95% CI: 1.01-5.49, p = 0.048). There was no difference in serum hormone levels between groups.

Conclusion: SMS reminder improved medication adherence in the short-term but had no effect on serum hormones levels in the longer term. Future studies could investigate the use of tailored SMS intervention according to patient preference to improve its sustainability.
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http://dx.doi.org/10.1016/j.breast.2020.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375684PMC
October 2020

Whole Exome Sequencing of Multi-Regional Biopsies from Metastatic Lesions to Evaluate Actionable Truncal Mutations Using a Single-Pass Percutaneous Technique.

Cancers (Basel) 2020 Jun 17;12(6). Epub 2020 Jun 17.

Department of Haematology-Oncology, National University Cancer Institute, Singapore 119074, Singapore.

We investigate the feasibility of obtaining multiple spatially-separated biopsies from a single lesion to explore intratumor heterogeneity and identify actionable truncal mutations using whole exome sequencing (WES). A single-pass radiologically-guided percutaneous technique was used to obtain four spatially-separated biopsies from a single metastatic lesion. WES was performed to identify putative truncal variants (PTVs), defined as a non-synonymous somatic (NSS) variant present in all four spatially separated biopsies. Actionable truncal mutations-filtered using the FoundationOne panel-were defined as clinically relevant PTVs. Mutational landscapes of each biopsy and their association with patient outcomes were assessed. WES on 50 biopsied samples from 13 patients across six cancer types were analyzed. Actionable truncal mutations were identified in 9/13 patients; 31.1 ± 5.12 more unique NSS variants were detected with every additional multi- region tumor biopsy (MRTB) analyzed. The number of PTVs dropped by 16.1 ± 17.9 with every additional MRTB, with the decrease most pronounced (36.8 ± 19.7) when two MRTB were analyzed compared to one. MRTB most reliably predicted PTV compared to in silico analysis of allele frequencies and cancer cell fraction based on one biopsy sample. Three patients treated with actionable truncal mutation-directed therapy derived clinical benefit Multi-regional sampling for genomics analysis is feasible and informative to help prioritize precision-therapy strategies.
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http://dx.doi.org/10.3390/cancers12061599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353029PMC
June 2020

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers.

Clin Cancer Res 2020 09 10;26(17):4494-4502. Epub 2020 Jun 10.

Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Purpose: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies.

Patients And Methods: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy.

Results: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB ( = 9) included multiple cycles of NK cells (1 × 10/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 10/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment.

Conclusions: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0768DOI Listing
September 2020

Tolerization of recent thymic emigrants is required to prevent RBC-specific autoimmunity.

J Autoimmun 2020 11 3;114:102489. Epub 2020 Jun 3.

Columbia University Irving Medical Center, Department of Pathology and Cell Biology, New York, NY, USA. Electronic address:

Autoimmune hemolytic anemia (AIHA) leads to accelerated destruction of autologous red blood cells (RBCs) by autoantibodies. AIHA is a severe and sometimes fatal disease. While there are several therapeutic strategies available, there are currently no licensed treatments for AIHA and few therapeutics result in treatment-free durable remission. The etiology of primary AIHA is unknown; however, secondary AIHA occurs concurrently with lymphoproliferative disorders and infections. Additionally, AIHA is the second most common manifestation of primary immunodeficiency disorders and has been described as a side effect of checkpoint inhibitor therapy. Given the severity of AIHA and the lack of treatment options, understanding the initiation of autoimmunity is imperative. Herein, we utilized a well-described model of RBC biology to dissect how RBC-specific autoreactive T cells become educated against RBC autoantigens. We show that, unlike most autoantigens, T cells do not encounter RBC autoantigens in the thymus. Instead, when they leave the thymus as recent thymic emigrants (RTEs), they retain the ability to positively respond to RBC autoantigens; only after several weeks in circulation do RTEs become nonresponsive. Together, these data suggest that any disruption in this process would lead to breakdown of tolerance and initiation of autoimmunity. Thus, RTEs and this developmental process are potential targets to prevent and treat AIHA.
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http://dx.doi.org/10.1016/j.jaut.2020.102489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572580PMC
November 2020

An international multicenter study of protocols for liver transplantation during a pandemic: A case for quadripartite equipoise.

J Hepatol 2020 10 23;73(4):873-881. Epub 2020 May 23.

National University Hospital, Singapore; SurgiCAL ProtEomics Laboratory, National University of Singapore, Singapore. Electronic address:

Background & Aims: The outbreak of COVID-19 has vastly increased the operational burden on healthcare systems worldwide. For patients with end-stage liver failure, liver transplantation is the only option. However, the strain on intensive care facilities caused by the pandemic is a major concern. There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources.

Methods: We performed an international multicenter study of transplant centers to understand the evolution of policies for transplant prioritization in response to the pandemic in March 2020. To describe the ethical tension arising in this setting, we propose a novel ethical framework, the quadripartite equipoise (QE) score, that is applicable to liver transplantation in the context of limited national resources.

Results: Seventeen large- and medium-sized liver transplant centers from 12 countries across 4 continents participated. Ten centers opted to limit transplant activity in response to the pandemic, favoring a "sickest-first" approach. Conversely, some larger centers opted to continue routine transplant activity in order to balance waiting list mortality. To model these and other ethical tensions, we computed a QE score using 4 factors - recipient outcome, donor/graft safety, waiting list mortality and healthcare resources - for 7 countries. The fluctuation of the QE score over time accurately reflects the dynamic changes in the ethical tensions surrounding transplant activity in a pandemic.

Conclusions: This four-dimensional model of quadripartite equipoise addresses the ethical tensions in the current pandemic. It serves as a universally applicable framework to guide regulation of transplant activity in response to the increasing burden on healthcare systems.

Lay Summary: There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources during the COVID-19 pandemic. We describe a four-dimensional model of quadripartite equipoise that models these ethical tensions and can guide the regulation of transplant activity in response to the increasing burden on healthcare systems.
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http://dx.doi.org/10.1016/j.jhep.2020.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245234PMC
October 2020

Small molecules, big effects: microbial metabolites in intestinal immunity.

Am J Physiol Gastrointest Liver Physiol 2020 05 6;318(5):G907-G911. Epub 2020 Apr 6.

Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania.

The mammalian intestine is host to a vast number of microbial organisms. The immune system must balance tolerance with innate and adaptive defense mechanisms to maintain homeostasis with the microbial community. Interestingly, microbial metabolites have been shown to play a role in shaping the host immune response, thus assisting with adaptations that have significant implications for human health and disease. New investigations have uncovered roles for metabolites in modulating almost every aspect of the immune system. In this minireview, we survey these recent findings, which taken together reveal nuanced interactions that we are just beginning to understand.
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http://dx.doi.org/10.1152/ajpgi.00263.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395478PMC
May 2020

Targeting Mitochondrial Apoptosis to Overcome Treatment Resistance in Cancer.

Cancers (Basel) 2020 Mar 2;12(3). Epub 2020 Mar 2.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.

Deregulated cellular apoptosis is a hallmark of cancer and chemotherapy resistance. The B-cell lymphoma 2 (BCL-2) protein family members are sentinel molecules that regulate the mitochondrial apoptosis machinery and arbitrate cell fate through a delicate balance between pro- and anti-apoptotic factors. The recognition of the anti-apoptotic gene as an oncogenic driver in hematological malignancies has directed attention toward unraveling the biological significance of each of the BCL-2 superfamily members in cancer progression and garnered interest in the targeting of apoptosis in cancer therapy. Accordingly, the approval of venetoclax (ABT-199), a small molecule BCL-2 inhibitor, in patients with chronic lymphocytic leukemia and acute myeloid leukemia has become the proverbial torchbearer for novel candidate drug approaches selectively targeting the BCL-2 superfamily. Despite the inspiring advances in this field, much remains to be learned regarding the optimal therapeutic context for BCL-2 targeting. Functional assays, such as through BH3 profiling, may facilitate prediction of treatment response, development of drug resistance and shed light on rational combinations of BCL-2 inhibitors with other branches of cancer therapy. This review summarizes the pathological roles of the BCL-2 family members in cancer, discusses the current landscape of their targeting in clinical practice, and highlights the potential for future therapeutic inroads in this important area.
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http://dx.doi.org/10.3390/cancers12030574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139457PMC
March 2020

A unique CDK4/6 inhibitor: Current and future therapeutic strategies of abemaciclib.

Pharmacol Res 2020 06 14;156:104686. Epub 2020 Feb 14.

Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore; Department of Pharmacology, National University of Singapore, Singapore; Department of Medicine, National University Cancer Institute Singapore, National University Health System, Singapore. Electronic address:

Cell cycle dysregulation, characterised by aberrant activation of cyclin dependent kinases (CDKs), is a hallmark of cancer. After years of research on the first and second generations of less selective CDK inhibitors with unfavourable clinical activity and toxicity profiles, CDK4/6 inhibitors become the first and only class of highly specific CDK inhibitors being approved for cancer treatment to date. CDK4/6 inhibitors have transformed the treatment paradigm of estrogen receptor-positive (ER+) breast cancer, dramatically improving the survival outcomes of these patients when incorporated with conventional endocrine therapies in both the first and later-line settings. Currently, the efficacies of CDK4/6 inhibitors in other breast cancer subtypes and cancers are being actively explored. All three CDK4/6 inhibitors have demonstrated very similar clinical efficacies. However, being the least similar structurally, abemaciclib is the only CDK4/6 inhibitor with single agent activity in refractory metastatic ER + breast cancer, the ability to cross the blood brain barrier efficiently, and a distinct toxicity profile of lower myelosuppression such that it can be dosed continuously. Here, we further discuss the distinguishing features of abemaciclib as compared to the other two CDK4/6 inhibitors, palbociclib and ribociclib. Besides being the most potent inhibitor of CDK4/6, abemaciclib exhibits a wider selectivity towards other CDKs and kinases, and functions through additional mechanisms of action besides inducing G1 cell cycle arrest, in a dose dependent manner. Hence, abemaciclib has the potential to act independently of the CDK4/6-cyclin D-RB pathway, resulting in crucial implications on the possibly expanded clinical indications and predictive biomarkers of abemaciclib, in contrast to the other CDK4/6 inhibitors. The current status of preclinical evidence and clinical studies of abemaciclib as a single agent and in combination treatment in breast and other cancers, together with its potential predictive biomarkers, is also summarised in this review.
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http://dx.doi.org/10.1016/j.phrs.2020.104686DOI Listing
June 2020

Targeting Cell Metabolism as Cancer Therapy.

Antioxid Redox Signal 2020 02 16;32(5):285-308. Epub 2019 Dec 16.

Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.

Cancer cells exhibit altered metabolic pathways to keep up with biosynthetic and reductionoxidation needs during tumor proliferation and metastasis. The common induction of metabolic pathways during cancer progression, regardless of cancer histio- or genotype, makes cancer metabolism an attractive target for therapeutic exploitation. Emerging data suggest that these altered pathways may even result in resistance to anticancer therapies. Identifying specific metabolic dependencies that are unique to cancer cells has proved challenging in this field, limiting the therapeutic window for many candidate drug approaches. Cancer cells display significant metabolic flexibility in nutrient-limited environments, hampering the longevity of suppressing cancer metabolism through any singular approach. Combinatorial "synthetic lethal" approaches may have a better chance for success and promising strategies are reviewed here. The dynamism of the immune system adds a level of complexity, as various immune populations in the tumor microenvironment often share metabolic pathways with cancer, with successive alterations during immune activation and quiescence. Decoding the reprogramming of metabolic pathways within cancer cells and stem cells, as well as examining metabolic symbiosis between components of the tumor microenvironment, would be essential to further meaningful drug development within the tumor's metabolic ecosystem. In this article, we examine evidence for the therapeutic potential of targeting metabolic alterations in cancer, and we discuss the drawbacks and successes that have stimulated this field.
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http://dx.doi.org/10.1089/ars.2019.7947DOI Listing
February 2020

MAIT cells are imprinted by the microbiota in early life and promote tissue repair.

Science 2019 10;366(6464)

Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T (MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)-producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1-, IL-18-, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury.
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http://dx.doi.org/10.1126/science.aax6624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603427PMC
October 2019

Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems.

Eur J Med Chem 2019 Dec 4;183:111674. Epub 2019 Sep 4.

Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D or D receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line.
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http://dx.doi.org/10.1016/j.ejmech.2019.111674DOI Listing
December 2019

Intradermal Synthetic DNA Vaccination Generates -Specific T Cells in the Skin and Protection against Leishmania major.

Infect Immun 2019 08 23;87(8). Epub 2019 Jul 23.

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Vaccination remains one of the greatest medical breakthroughs in human history and has resulted in the near eradication of many formerly lethal diseases in many countries, including the complete eradication of smallpox. However, there remain a number of diseases for which there are no or only partially effective vaccines. There are numerous hurdles in vaccine development, of which knowing the appropriate immune response to target is one of them. Recently, tissue-resident T cells have been shown to mediate high levels of protection for several infections, although the best way to induce these cells is still unclear. Here we compare the ability to generate skin-resident T cells in sites distant from the immunization site following intramuscular and intradermal injection using optimized synthetic DNA vaccines. We found that mice immunized intradermally with a synthetic consensus DNA HIV envelope vaccine by electroporation (EP) are better able to maintain durable antigen-specific cellular responses in the skin than mice immunized by the intramuscular route. We extended these studies by delivering a synthetic DNA vaccine encoding glycosomal phosphoenolpyruvate carboxykinase (PEPCK) by EP and again found that the intradermal route was superior to the intramuscular route for generating skin-resident PEPCK-specific T cells. We observed that when challenged with parasites, mice immunized intradermally exhibited significant protection, while mice immunized intramuscularly did not. The protection seen in intradermally vaccinated mice supports the viability of this platform not only to generate skin-resident T cells but also to promote durable protective immune responses at relevant tissue sites.
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http://dx.doi.org/10.1128/IAI.00227-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652766PMC
August 2019

New Approaches to Microbiome-Based Therapies.

mSystems 2019 Jun 4;4(3). Epub 2019 Jun 4.

Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Over the last decade, our understanding of the composition and functions of the gut microbiota has greatly increased. To a large extent, this has been due to the development of high-throughput genomic analyses of microbial communities, which have identified the critical contributions of the microbiome to human health. Consequently, the intestinal microbiota has emerged as an attractive therapeutic target. The large majority of microbiota-targeted therapies aim at engineering the intestinal ecosystem by means of probiotics or prebiotics. Recently, a novel therapeutic approach has emerged which focuses on molecules that are secreted, modulated, or degraded by the microbiome and act directly on the host. Here, we discuss the advantages and challenges associated with the metabolite-based "postbiotic" approach, highlighting recent progress and the areas that need intensive attention and investigation over the next 5 years. The time is ripe for postbiotic therapies to be developed in the near future.
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http://dx.doi.org/10.1128/mSystems.00122-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584878PMC
June 2019

Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential.

Cancer 2019 06 1;125(11):1789-1798. Epub 2019 Apr 1.

Cancer Science Institute of Singapore, National University of Singapore, Singapore.

Deguelin is a rotenoid compound that exists in abundant quantities in the bark, roots, and leaves of the Leguminosae family of plants. An analysis of evidence from both in vitro and in vivo studies suggests that deguelin displays potent anticancer activity against multiple cancer types and exhibits chemopreventive potential in Akt-inducible transgenic mouse models. Deguelin appears to impede carcinogenesis by enhancing cell apoptosis and hindering malignant transformation and tumor cell propagation. Crucial oncogenic pathways likely targeted by deguelin include the epithelial-to-mesenchymal transition; angiogenesis-related pathways; and the phosphoinositide 3-kinase/Akt, Wnt, epidermal growth factor receptor, c-Met, and hedgehog signal transduction cascades. This review article provides a comprehensive summary of current preclinical research featuring deguelin as a leading chemotherapeutic and chemopreventive compound, and it highlights the importance of identifying companion molecular biomarkers and performing systemic pharmacokinetic studies for accelerating the process of developing deguelin as a clinical anticancer agent.
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http://dx.doi.org/10.1002/cncr.32069DOI Listing
June 2019

Familial Alzheimer's disease-linked presenilin mutants and intracellular Ca handling: A single-organelle, FRET-based analysis.

Cell Calcium 2019 05 23;79:44-56. Epub 2019 Feb 23.

Neuroscience Institute - Italian National Research Council (CNR), 35131 Padua, Italy; Department of Biomedical Sciences, University of Padua, Via U. Bassi 58/B, 35131 Padua, Italy.

An imbalance in Ca homeostasis represents an early event in the pathogenesis of Alzheimer's disease (AD). Presenilin-1 and -2 (PS1 and PS2) mutations, the major cause of familial AD (FAD), have been extensively associated with alterations in different Ca signaling pathways, in particular those handled by storage compartments. However, FAD-PSs effect on organelles Ca content is still debated and the mechanism of action of mutant proteins is unclear. To fulfil the need of a direct investigation of intracellular stores Ca dynamics, we here present a detailed and quantitative single-cell analysis of FAD-PSs effects on organelle Ca handling using specifically targeted, FRET (Fluorescence/Förster Resonance Energy Transfer)-based Ca indicators. In SH-SY5Y human neuroblastoma cells and in patient-derived fibroblasts expressing different FAD-PSs mutations, we directly measured Ca concentration within the main intracellular Ca stores, e.g., Endoplasmic Reticulum (ER) and Golgi Apparatus (GA) medial- and trans-compartment. We unambiguously demonstrate that the expression of FAD-PS2 mutants, but not FAD-PS1, in either SH-SY5Y cells or FAD patient-derived fibroblasts, is able to alter Ca handling of ER and medial-GA, but not trans-GA, reducing, compared to control cells, the Ca content within these organelles by partially blocking SERCA (Sarco/Endoplasmic Reticulum Ca-ATPase) activity. Moreover, by using a cytosolic Ca probe, we show that the expression of both FAD-PS1 and -PS2 reduces the Ca influx activated by stores depletion (Store-Operated Ca Entry; SOCE), by decreasing the expression levels of one of the key molecules, STIM1 (STromal Interaction Molecule 1), controlling this pathway. Our data indicate that FAD-linked PSs mutants differentially modulate the Ca content of intracellular stores yet leading to a complex dysregulation of Ca homeostasis, which represents a common disease phenotype of AD.
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http://dx.doi.org/10.1016/j.ceca.2019.02.005DOI Listing
May 2019

Understanding the cancer stem cell phenotype: A step forward in the therapeutic management of cancer.

Biochem Pharmacol 2019 04 25;162:79-88. Epub 2019 Jan 25.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Medical Science Cluster Cancer Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Cancer Institute, National University Health System, Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore. Electronic address:

The experimental validation of the existence of cancer stem cells (CSC) has had a significant impact on our understanding of the cellular mechanisms and signaling networks involved in the process of carcinogenesis and its progression. These findings provide insights into the critical role that tumor microenvironment and metabolism play in the acquisition of the drug resistance phenotype as well as provide potential targets for therapeutic exploitation. Here we briefly review the literature on the involvement of key signaling pathways such as Wnt/β-catenin, Notch, Hedgehog and STAT3 in the appearance of cancer cells with stem cells-like characteristics. In addition, we also highlight some of the recent therapeutic strategies used to target these pathways as well as approaches aiming to specifically target CSCs through their distinctive metabolic features.
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http://dx.doi.org/10.1016/j.bcp.2019.01.020DOI Listing
April 2019

Alloimmunogenicity of an isolated MHC allele is affected by the context of MHC mismatch in a murine model.

Transfusion 2019 02 25;59(2):744-753. Epub 2019 Jan 25.

BloodworksNW Research Institute, Seattle, Washington.

Background: Humoral alloimmunization to human leukocyte antigen (HLA) can represent a barrier to solid-organ transplantation, can lead to a refractory state in patients requiring platelet transfusion, and can also contribute to transfusion-related acute lung injury (TRALI). While exposure to HLA-mismatched cells/tissues are generally required for HLA alloimmunization, the effect of the extent of major histocompatibility complex (MHC) mismatch between donor and recipient is poorly understood.

Study Design And Methods: A novel mouse was generated that allows the expression of a single MHC Class I alloantigen, K . Alloimmune responses to K were studied in C57BL/6 mice transfused with splenocytes from different donor mice, allowing the analysis of responses to K as an isolated alloantigen, or in the context of additional mismatched MHC molecules. Advanced tools were utilized to study responses to K , including T-cell receptor transgenic mice that recognize the immunodominant K peptide presented by C57BL/6 mice to CD4+ T cells.

Results: A single MHC Class I alloantigen mismatch is less immunogenic than when the same alloantigen is encountered in the context of additional mismatched MHC alloantigens. This difference is due, at least in part, to induction of CD4+ helper T cells, as the effect is overcome by increasing either mature CD4+ T-cell help through immunization or by increasing the precursor frequency of naïve CD4+ T cells by adoptive transfer from T-cell receptor transgenic donors.

Conclusion: These findings indicate that the immunogenicity of a single alloantigen can be affected by the context in which it is encountered, demonstrating the potential for cooperative effects between different mismatched MHC alloantigens.
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http://dx.doi.org/10.1111/trf.15109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025900PMC
February 2019

Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance.

Redox Biol 2019 07 17;25:101076. Epub 2018 Dec 17.

Department of Physiology and Medical Science Cluster Cancer ProgramYong Loo Lin School of Medicine, National University of Singapore, Singapore 119753, Singapore; NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456, Singapore; National University Cancer Institute, National University Health System, Singapore 119074, Singapore; Curtin Health Innovation Research Institute and School of Pharmacy and Biomedical Sciences, Curtin University, Perth 6102, Australia. Electronic address:

The ability to selectively eradicate oncogene-addicted tumors while reducing systemic toxicity has endeared targeted therapies as a treatment strategy. Nevertheless, development of acquired resistance limits the benefits and durability of such a regime. Here we report evidence of enhanced reliance on mitochondrial oxidative phosphorylation (OXPHOS) in oncogene-addicted cancers manifesting acquired resistance to targeted therapies. To that effect, we describe a novel OXPHOS targeting activity of the small molecule compound, OPB-51602 (OPB). Of note, a priori treatment with OPB restored sensitivity to targeted therapies. Furthermore, cancer cells exhibiting stemness markers also showed selective reliance on OXPHOS and enhanced sensitivity to OPB. Importantly, in a subset of patients who developed secondary resistance to EGFR tyrosine kinase inhibitor (TKI), OPB treatment resulted in decrease in metabolic activity and reduction in tumor size. Collectively, we show here a switch to mitochondrial OXPHOS as a key driver of targeted drug resistance in oncogene-addicted cancers. This metabolic vulnerability is exploited by a novel OXPHOS inhibitor, which also shows promise in the clinical setting.
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http://dx.doi.org/10.1016/j.redox.2018.101076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859574PMC
July 2019

Targeting STAT3 and oxidative phosphorylation in oncogene-addicted tumors.

Redox Biol 2019 07 13;25:101073. Epub 2018 Dec 13.

Department of Haematology-Oncology, National University Health System, Singapore; Haematology-Oncology Research Group, National University Cancer Institute of Singapore, National University Health System, Singapore; Cancer Science Institute, Singapore. Electronic address:

Drug resistance invariably limits the response of oncogene-addicted cancer cells to targeted therapy. The upregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a mechanism of drug resistance in a range of oncogene-addicted cancers. However, the development of inhibitors against STAT3 has been fraught with challenges such as poor delivery or lack of specificity. Clinical experience with small molecule STAT3 inhibitors has seen efficacy signals, but this success has been tempered by drug limiting toxicities from off-target adverse events. It has emerged in recent years that, contrary to the Warburg theory, certain tumor types undergo metabolic reprogramming towards oxidative phosphorylation (OXPHOS) to satisfy their energy production. In particular, certain drug-resistant oncogene-addicted tumors have been found to rely on OXPHOS as a mechanism of survival. Multiple cellular signaling pathways converge on STAT3, hence the localization of STAT3 to the mitochondria may provide the link between oncogene-induced signaling pathways and cancer cell metabolism. In this article, we review the role of STAT3 and OXPHOS as targets of novel therapeutic strategies aimed at restoring drug sensitivity in treatment-resistant oncogene-addicted tumor types. Apart from drugs which have been re-purposed as OXPHOS inhibitors for-anti-cancer therapy (e.g., metformin and phenformin), several novel compounds in the drug-development pipeline have demonstrated promising pre-clinical and clinical activity. However, the clinical development of OXPHOS inhibitors remains in its infancy. The further identification of compounds with acceptable toxicity profiles, alongside the discovery of robust companion biomarkers of OXPHOS inhibition, would represent tangible early steps in transforming the therapeutic landscape of cancer cell metabolism.
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http://dx.doi.org/10.1016/j.redox.2018.101073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859582PMC
July 2019

A Review on Liquid Chromatography-Tandem Mass Spectrometry Methods for Rapid Quantification of Oncology Drugs.

Pharmaceutics 2018 Nov 8;10(4). Epub 2018 Nov 8.

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.

In the last decade, the tremendous improvement in the sensitivity and also affordability of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has revolutionized its application in pharmaceutical analysis, resulting in widespread employment of LC-MS/MS in determining pharmaceutical compounds, including anticancer drugs in pharmaceutical research and also industries. Currently, LC-MS/MS has been widely used to quantify small molecule oncology drugs in various biological matrices to support preclinical and clinical pharmacokinetic studies in R&D of oncology drugs. This mini-review article will describe the state-of-the-art LC-MS/MS and its application in rapid quantification of small molecule anticancer drugs. In addition, efforts have also been made in this review to address several key aspects in the development of rapid LC-MS/MS methods, including sample preparation, chromatographic separation, and matrix effect evaluation.
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http://dx.doi.org/10.3390/pharmaceutics10040221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321130PMC
November 2018