ORCID Profile
0000-0002-6394-0011
Current Organisation
Peter MacCallum Cancer Centre
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Publisher: American Association for Cancer Research (AACR)
Date: 11-02-2022
DOI: 10.1158/0008-5472.CAN-21-2062
Abstract: This study characterizes metabolic changes during cancer metastasis and identifies GAPDHS as a novel regulator of these processes in melanoma cells.
Publisher: Elsevier BV
Date: 10-2013
Abstract: Suicide rates among patients with lung cancer are higher than the general population. This study aims to identify patient and disease characteristics associated with suicide in patients with lung cancer. We conducted an analysis of subjects with primary lung cancer diagnosed between 1973 and 2008 recorded in the Surveillance, Epidemiology and End Results database. From 871,230 people diagnosed with lung cancer, 1,184 cases of suicide were identified. The rate of suicide did not change considerably over time, with 8.83 compared with 7.17 suicides per 10,000 person-years in 1973 to 1979 and 2000 to 2009, respectively. The standardized mortality ratio (SMR) of the entire cohort was 4.95, with an SMR of 13.4 within 3 months of a cancer diagnosis. Despite most subgroups having a higher SMR than the general population, a wide variation in suicide risk was seen among different subgroups, including histologic type (SMR 1.58 vs 7.28 in bronchoalveolar and small cell carcinoma, respectively). The highest SMRs were found in patients with the following characteristics: male, older age, higher-grade tumor, and metastatic disease, and in patients who did not receive or refused treatment. Despite the higher SMR among patients with metastatic disease, 50% of suicides occurred in those with locoregional and potentially curable disease. Patients with lung cancer have a higher risk for suicide compared with the general US population, especially within 3 months of diagnosis. Despite the higher SMR among patients with a poorer prognosis, a concerning proportion of suicides occurs in potentially curable patients, highlighting the need for effective screening strategies to avoid this preventable cause of death.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.PHRS.2016.02.009
Abstract: Metabolic reprogramming is a recognized hallmark of cancer. In order to support continued proliferation and growth, tumor cells must metabolically adapt to balance their bioenergetic and biosynthetic needs. To achieve this, cancer cells switch from mitochondrial oxidative phosphorylation to predominantly rely on glycolysis, a process known as the "Warburg effect". The BRAF oncogene has recently emerged as a critical regulator of this process in melanoma, bringing to the fore the importance of metabolic reprogramming in the pathogenesis and treatment of metastatic melanoma. In this review, we summarize our current understanding of oncogenic reprogramming of metabolism in BRAF and NRAS mutant melanoma, and highlight emerging evidence supporting a metabolic basis for MAPK pathway inhibitor resistance and metabolic vulnerabilities that may be exploited to overcome this.
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.CANLET.2013.09.040
Abstract: Physiological processes such as the sleep-wake cycle, metabolism and hormone secretion are controlled by a circadian rhythm adapted to 24h day-night periodicity. This circadian synchronisation is in part controlled by ambient light decreasing melatonin secretion by the pineal gland and co-ordinated by the suprachiasmatic nucleus of the hypothalamus. Peripheral cell autonomous circadian clocks controlled by the suprachiasmatic nucleus, the master regulator, exist within every cell of the body and are comprised of at least twelve genes. These include the basic helix-loop-helix/PAS domain containing transcription factors Clock, BMal1 and Npas2 which activate transcription of the periodic genes (Per1 and Per2) and cryptochrome genes (Cry1 and Cry2). Points of coupling exist between the cellular clock and the cell cycle. Cell cycle genes which are affected by the molecular circadian clock include c-Myc, Wee1, cyclin D and p21. Therefore the rhythm of the circadian clock and cancer are interlinked. Molecular ex les exist including activation of Per2 leads to c-myc overexpression and an increased tumor incidence. Mice with mutations in Cryptochrome 1 and 2 are arrhythmic (lack a circadian rhythm) and arrhythmic mice have a faster rate of growth of implanted tumors. Epidemiological finding of relevance include 'The Nurses' Health Study' where it was established that women working rotational night shifts have an increased incidence of breast cancer. Compounds that affect circadian rhythm exist with attendant future therapeutic possibilities. These include casein kinase I inhibitors and a candidate small molecule KL001 that affects the degradation of cryptochrome. Theoretically the cell cycle and malignant disease may be targeted vicariously by selective alteration of the cellular molecular clock.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2019
Publisher: Wiley
Date: 28-07-2014
DOI: 10.1111/EJH.12404
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2014
Publisher: Cold Spring Harbor Laboratory
Date: 11-2022
DOI: 10.1101/2022.10.31.514397
Abstract: Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed metabolism in patient-derived xenografts (tumorgrafts) from erse forms of RCC. Tumorgrafts from VHL -mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engage in oxidative and reductive glutamine metabolism. We used several approaches to suppress glutamine metabolism and test the effect on tumor growth. Genetic silencing of isocitrate dehydrogenase-1 or -2 impaired reductive labeling of TCA cycle intermediates and suppressed tumor growth. Glutaminase inhibition resulted in modest growth suppression and variable effects on glutamine metabolism in vivo. Infusions with [amide- 15 N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase. Glutamine fuels the TCA cycle and amidotransferase pathways in clear cell renal cell carcinoma.
Publisher: Springer Science and Business Media LLC
Date: 06-04-2022
DOI: 10.1038/S41586-022-04557-9
Abstract: Mammalian embryogenesis requires rapid growth and proper metabolic regulation 1 . Midgestation features increasing oxygen and nutrient availability concomitant with fetal organ development 2,3 . Understanding how metabolism supports development requires approaches to observe metabolism directly in model organisms in utero. Here we used isotope tracing and metabolomics to identify evolving metabolic programmes in the placenta and embryo during midgestation in mice. These tissues differ metabolically throughout midgestation, but we pinpointed gestational days (GD) 10.5–11.5 as a transition period for both placenta and embryo. Isotope tracing revealed differences in carbohydrate metabolism between the tissues and rapid glucose-dependent purine synthesis, especially in the embryo. Glucose’s contribution to the tricarboxylic acid (TCA) cycle rises throughout midgestation in the embryo but not in the placenta. By GD12.5, compartmentalized metabolic programmes are apparent within the embryo, including different nutrient contributions to the TCA cycle in different organs. To contextualize developmental anomalies associated with Mendelian metabolic defects, we analysed mice deficient in LIPT1, the enzyme that activates 2-ketoacid dehydrogenases related to the TCA cycle 4,5 . LIPT1 deficiency suppresses TCA cycle metabolism during the GD10.5–GD11.5 transition, perturbs brain, heart and erythrocyte development and leads to embryonic demise by GD11.5. These data document in idualized metabolic programmes in developing organs in utero.
Publisher: Springer Science and Business Media LLC
Date: 03-2022
DOI: 10.1038/S41467-022-28705-X
Abstract: Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-09-2022
Abstract: In mice and humans with cancer, intravenous 13 C-glucose infusion results in 13 C labeling of tumor tricarboxylic acid (TCA) cycle intermediates, indicating that pyruvate oxidation in the TCA cycle occurs in tumors. The TCA cycle is usually coupled to the electron transport chain (ETC) because NADH generated by the cycle is reoxidized to NAD + by the ETC. However, 13 C labeling does not directly report ETC activity, and other pathways can oxidize NADH, so the ETC’s role in these labeling patterns is unverified. We examined the impact of the ETC complex I inhibitor IACS-010759 on tumor 13 C labeling. IACS-010759 suppresses TCA cycle labeling from glucose or lactate and increases labeling from glutamine. Cancer cells expressing yeast NADH dehydrogenase-1, which recycles NADH to NAD + independently of complex I, display normalized labeling when complex I is inhibited, indicating that cancer cell ETC activity regulates TCA cycle metabolism and 13 C labeling from multiple nutrients.
Publisher: Proceedings of the National Academy of Sciences
Date: 22-08-2019
Abstract: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5–MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5–MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2014
DOI: 10.1007/S00259-014-2888-2
Abstract: Small cell cancers (SmCC), whether pulmonary (SCLC) or extrapulmonary, have a poor prognosis unless localised at diagnosis. Given a proportion of these cancers express somatostatin receptor subtype 2 (SSTR2), we aimed to investigate the efficacy of targeted peptide receptor chemoradionuclide therapy (PRCRT). In this preclinical study, we used a SCLC xenograft mouse model with high expression of SSTR2 to investigate the effect of peptide receptor radionuclide therapy (PRRT) with chemotherapy compared to either alone. We subsequently explored the clinical utility in a patient with SmCC with high SSTR expression treated with PRCRT. Robust expression of SSTR2 in NCI-H69 SCLC xenografts was documented by (68)Ga-DOTA-octreotate (GaTate) (tumour to background uptake ratio = 35). The combination of PRRT using (177)Lu-DOTA-octreotate (LuTate) with carboplatin/etoposide (C/E) chemotherapy was more effective than either LuTate or C/E alone for regression of the NCI-H69 model (p value < 0.05). PRCRT was associated with significantly prolonged survival versus PRRT (p value = 0.0001) or chemotherapy alone (p value = 0.0058). In the subsequent case study, a patient with relapsed SmCC with high SSTR2 expression on GaTate PET underwent PRCRT with radiosensitising etoposide with evidence of a complete metabolic response for 4 months. Given the limited treatment options in this setting, PRCRT is a promising therapeutic option for SSTR2-expressing SmCC.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 16-12-2022
Abstract: Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from erse subtypes of RCC. Tumorgrafts from VHL -mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide- 15 N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2014
DOI: 10.1158/2159-8290.CD-13-0440
Abstract: Deregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF-mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF-mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including hypoxia-inducible factor-1α, MYC, and MONDOA (MLXIP), drives glycolysis downstream of BRAFV600, is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)–resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors. Significance: BRAFis suppress glycolysis and provide strong clinical benefit in BRAFV600 melanoma. We show that BRAF inhibition suppresses glycolysis via a network of transcription factors that are critical for complete BRAFi responses. Furthermore, we provide evidence for the clinical potential of therapies that combine BRAFis with glycolysis inhibitors. Cancer Discov 4(4) 423–33. ©2014 AACR. See related commentary by Haq, p. 390 This article is highlighted in the In This Issue feature, p. 377
No related grants have been discovered for Aparna Dodla Rao.