Dr Agnieszka Michael

Senior Lecturer

Qualifications: MD PhD

Email:
Phone: Work: 01483 68 8546
Room no: 04 PGM 03

Office hours

9am-5pm Mon-Fri

Further information

Biography

Qualifications

 

PhD October 2006

                                              

MRCP UK July 1998 London

                                              

PLAB October 1995 London

                                            

MBBS June 1993 Medical School Wroclaw Poland

 

Previous Positions

 

05 SEPT’ 06- 09 DEC’07            Guy’s and St Thomas’ NHS FT, Specialist Registrar rotation

05 MAR’ 06- 04 SEPT’ 06           St George’s Hospital, Haemato-Oncology, Specialist Registrar

05 SEPT’ 05- 04 MARCH’ 06        Guy’s and St.Thomas’ NHS FT, Specialist Registrar                                             

01 JUL’ 05 - 04 SEPT’ 05             St George’s Hospital London, Specialist Registrar                                             

01 MAY’ 01 – 30 OCT’ 04           Clinical research fellow , PhD project, 

01 JUNE’ 99-30 APRIL’ 01        St. George’s Hospital, Specialist Registrar rotation                                                 

01 APR’ 99-30 MAY’ 99            Royal Marsden Hospital, Breast Unit, Specialist Registrar

                                   

SHO posts:

AUG’ 98-FEB’ 99                       Royal Marsden Hospital, Sutton,

FEB’ 96-AUG’ 98                      Two-year medical rotation in Havering Hospitals in Essex.

Research Interests

Biomarkers for Cancer 

Ovarian Cancer

Publications

Journal articles

  • Annels NE, Simpson GR, Denyer M, McGrath SE, Falgari G, Killick E, Eeles R, Stebbing J, Pchejetski D, Cutress R, Murray N, Michael A, Pandha H. (2014) 'Spontaneous antibodies against Engrailed-2 (EN2) protein in patients with prostate cancer.'. Clin Exp Immunol,

    Abstract

    We reported the expression of the homeodomain-containing transcription factor Engrailed-2 (EN2) in prostate cancer and showed that the presence of EN2 protein in the urine was highly predictive of prostate cancer. This study aimed to determine whether patients with prostate cancer have EN2 auto-antibodies, what the prevalence of these antibodies is and whether they are associated with disease stage. The spontaneous IgG immune response against EN2 and for comparison the tumour antigen NY-ESO-1, were tested by ELISA in three different cohorts of prostate cancer patients as well as a group of men genetically predisposed to prostate cancer. 32/353 (9.1%) of the SUN cohort representing all stages of prostate cancer demonstrated EN2 IgG responses, 12/107 patients (11.2%) in the advanced prostate cancer patients showed responses, whilst only 4/121 patients (3.3%) with castrate resistant prostate cancer showed EN2 auto-antibodies. No significant responses were found in the predisposed group. Anti-EN2 IgG responses were significantly higher in patients with prostate cancer compared to healthy control males and similarly prevalent to anti-NY-ESO-1 responses. Whilst EN2 autoantibodies are not a useful diagnostic or monitoring tool EN2 immunogenicity does provide the rationale to pursue studies using EN2 as an immunotherapeutic target.

  • Morgan R, Boxall A, Harrington KJ, Simpson GR, Michael A, Pandha HS. (2014) 'Targeting HOX transcription factors in prostate cancer.'. BMC Urol, England: 14

    Abstract

    The HOX genes are a family of transcription factors that help to determine cell and tissue identity during early development, and which are also over-expressed in a number of malignancies where they have been shown to promote cell proliferation and survival. The purpose of this study was to evaluate the expression of HOX genes in prostate cancer and to establish whether prostate cancer cells are sensitive to killing by HXR9, an inhibitor of HOX function.

  • McGrath SE, Michael A, Morgan R, Pandha H. (2013) 'EN2: a novel prostate cancer biomarker.'. Biomark Med, England: 7 (6), pp. 893-901.

    Abstract

    Extensive efforts to identify a clinically useful biomarker for the diagnosis of prostate cancer have resulted in important insights into the biology of the disease, but no new test has been approved by regulatory authorities. The unmet need has also shifted to identifying biomarkers that not only diagnose prostate cancer but also indicate whether the patient has 'significant' disease. EN2 is a homeobox-containing transcription factor secreted specifically by prostate cancers into urine, where it can be detected by a simple ELISA assay. A number of studies have demonstrated the enormous potential of EN2 to address this unmet need and provide the urologist with a simple, cheap and efficient prostate cancer biomarker.

  • McGrath SE, Michael A, Pandha H, Morgan R. (2013) 'Engrailed homeobox transcription factors as potential markers and targets in cancer'. FEBS Letters, 587 (6), pp. 549-554.

    Abstract

    Engrailed (En) is a member of the homeobox gene family, which encodes a homeodomain-containing transcription factor that is essential during early development. The only known site of normal adult Engrailed protein (EN) expression is in the nervous system, and it has been implicated in the development of both young-onset Parkinson's disease as well as autism. Over-expression of EN has been linked to tumour development in adults, particularly in breast, prostate, melanoma and ovarian cancers, and there is a growing interest in its role as a diagnostic and prognostic biomarker. It is hoped that further work may confirm associations between En expression and therapy-resistant, poor prognosis cancers, similar to that identified with other homeobox gene profiles. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  • McGrath SE, Michael A, Pandha H, Morgan R. (2013) 'Engrailed homeobox transcription factors as potential markers and targets in cancer.'. FEBS Lett, Netherlands: 587 (6), pp. 549-554.

    Abstract

    Engrailed (En) is a member of the homeobox gene family, which encodes a homeodomain-containing transcription factor that is essential during early development. The only known site of normal adult Engrailed protein (EN) expression is in the nervous system, and it has been implicated in the development of both young-onset Parkinson's disease as well as autism. Over-expression of EN has been linked to tumour development in adults, particularly in breast, prostate, melanoma and ovarian cancers, and there is a growing interest in its role as a diagnostic and prognostic biomarker. It is hoped that further work may confirm associations between En expression and therapy-resistant, poor prognosis cancers, similar to that identified with other homeobox gene profiles.

  • Michael A, Relph K, Annels N, Pandha H. (2013) 'Prostate cancer vaccines.'. Expert Rev Vaccines, England: 12 (3), pp. 253-262.

    Abstract

    In 2010, the US FDA approved the first therapeutic cancer vaccine for the treatment of castration refractory prostate cancer - sipuleucel-T. Prostate cancer is an ideal model for cancer vaccine development based on the ready demonstration of humoral and cellular immunity to a range of cancer antigens as well as often slow progression which means that patients who are otherwise well may have a radiologically evaluable minor progression, after conventional treatment and can undergo vaccine therapy over sufficient periods of time, so as to allow the generation of a robust antitumor response. The association of prostate cancer with one of the few serum cancer biomarkers in general use has also allowed assessment of response and risk stratification of patients. In this review, we will examine key aspects of the evolution of prostate cancer vaccines, which provides an accurate prototype for other cancers, and the challenges we face.

  • Larbi E, Madhuri K, Essapen S, Butler-Manuel S, Tailor A, Michael A. (2013) 'The Effect of Age on First-line Chemotherapy for Epithelial Ovarian Cancer and Primary Peritoneal Carcinoma'. Clinical Oncology, 25 (1), pp. 75-75.
  • Larbi E, Madhuri K, Essapen S, Butler-Manuel S, Tailor A, Michael A. (2012) 'The Effect of Age on First-line Chemotherapy for Epithelial Ovarian Cancer and Primary Peritoneal Carcinoma'. Clinical Oncology,
  • Morgan R, Boxall A, Simpson GR, Michael A, Pandha HS, Harrington KJ, Gillett C. (2012) 'Targeting the HOX/PBX dimer in breast cancer'. Breast Cancer Research and Treatment, 136 (2), pp. 389-398.

    Abstract

    The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. While relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumor suppressors, and also redundant, with several genes essentially having the same function. Here, we have attempted to address this complexity using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumors to HXR9 or its derivatives. Measuring the expression of HOX genes HOXB1-HOXB9 in primary tumors revealed that a subset of tumors show highly elevated expression indicating that these might be potentially very sensitive to killing by HXR9. Furthermore, we show that while HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumor-suppressor properties of a subset of HOX genes in breast cancer. © Springer Science+Business Media New York 2012.

  • Morgan R, Boxall A, Harrington KJ, Simpson GR, Gillett C, Michael A, Pandha HS. (2012) 'Targeting the HOX/PBX dimer in breast cancer.'. Springer Breast Cancer Res Treat, Netherlands: 136 (2), pp. 389-398.

    Abstract

    The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. While relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumor suppressors, and also redundant, with several genes essentially having the same function. Here, we have attempted to address this complexity using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumors to HXR9 or its derivatives. Measuring the expression of HOX genes HOXB1-HOXB9 in primary tumors revealed that a subset of tumors show highly elevated expression indicating that these might be potentially very sensitive to killing by HXR9. Furthermore, we show that while HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumor-suppressor properties of a subset of HOX genes in breast cancer.

  • McGrath S, Madhuri TK, Susarla S, Haagsma B, Saleh F, Michael A. (2012) 'Low grade serous ovarian carcinoma with metastases to the sternum and ribs.'. Pathology, England: 44 (5), pp. 481-482.
  • Chen SS, Michael A, Butler-Manuel SA. (2012) 'Advances in the treatment of ovarian cancer: a potential role of antiinflammatory phytochemicals.'. Discov Med, United States: 13 (68), pp. 7-17.

    Abstract

    Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies worldwide. The five-year survival rates for stage IIIC and IV patients are 29% and 13%, respectively. Type-2 EOC cells have been found to be associated with this late stage disease. In contrast, women diagnosed in stage 1 disease, which mostly exhibits type-1 cells, have a high 5-year survival rate (90%). Recent progress in understanding the pathogenesis of EOC and inflammatory signaling pathways revealed that type-2 cells frequently express a deleted or mutated TP53 (60-80%), or aberrations in BRCA1 (30-60%) and BRCA2 (15-30%). The deletion or mutation of TP53 results in a dysregulated inflammatory signal network and contributes to an immunosuppressive microenvironment. Thus, to be effective, EOC therapy may be necessary to cover two areas: (1) direct cytotoxic killing of cancer cells; (2) reversion of the immunosuppressive microenvironment. Presently the first strategy is advancing rapidly while the second strategy remains behind. Isolation and characterization of cancer stem cells (CSCs) have helped to confirm the dynamic role of the tumor microenvironment in promoting cancer metastasis and recurrence. Based on widely published in vitro and mouse-model data, some anti-inflammatory phytochemicals appear to exhibit activity in modulating the tumor microenvironment. Specifically, apiegenin, baicalein, curcumin, EGCG, genistein, luteolin, oridonin, quercetin, and wogonin repress NF-kappaB (NF-κB, a proinflammatory transcription factor) and inhibit proinflammatory cytokines such as TNF-α and IL-6. Additionally, most of these phytochemicals have been shown to stabilize p53 protein, sensitize TRAIL (TNF receptor apoptosis-inducing ligand) induced apoptosis, and prevent or delay chemotherapy-resistance. Recent studies further indicate that apigenin, genistein, kaempferol, luteolin, and quercetin potently inhibit VEGF production and suppress ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted.

  • Michael A, Riley C, Bokaee S, Denyer M, Pandha HS, Annels NE. (2011) 'EN2: A candidate antigen for the development of targeted therapies in ovarian cancer.'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, 29 (15)
  • Morgan RM, Ismail M, Boxall A, Bhaat A, Hindley R, Michael A, Langley SM, Zylstra J, Pandha HS. (2011) 'ENGRAILED-2 (EN2): A HIGHLY SPECIFIC URINARY BIOMARKER FOR THE EARLY DIAGNOSIS OF PROSTATE CANCER'. ELSEVIER SCIENCE BV EUR UROL SUPPL, 10 (2), pp. 64-64.
  • Morgan R, Boxall A, Bhatt A, Bailey M, Hindley R, Langley S, Whitaker HC, Neal DE, Ismail M, Whitaker H, Annels N, Michael A, Pandha H. (2011) 'Engrailed-2 (EN2): a tumor specific urinary biomarker for the early diagnosis of prostate cancer.'. Clin Cancer Res, United States: 17 (5), pp. 1090-1098.

    Abstract

    Prostate cancer (PC) is the second most common cause of cancer related death in men. A number of key limitations with prostate specific antigen (PSA), currently the standard detection test, has justified evaluation of new biomarkers. We have assessed the diagnostic potential of Engrailed-2 (EN2) protein, a homeodomain-containing transcription factor expressed in PC cell lines and secreted into the urine by PC in men.

  • Kelly ZL, Michael A, Butler-Manuel S, Pandha HS, Morgan RG. (2011) 'HOX genes in ovarian cancer'. Springer Journal of Ovarian Research, 4 (1)

    Abstract

    The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease.

  • Gray S, Pandha HS, Michael A, Middleton G, Morgan R. (2011) 'HOX genes in pancreatic development and cancer.'. JOP, Italy: 12 (3), pp. 216-219.

    Abstract

    The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are subsequently re-expressed in many types of cancer. Some recent studies have shown that HOX genes may have key roles both in pancreatic development and in adult diseases of the pancreas, including cancer. In this review we consider recent advances in elucidating the role of HOX genes in these processes, how they may connect early developmental events to subsequent adult disease, and their potential both as diagnostic markers and therapeutic targets.

  • Michael A, Relph K, Pandha H. (2010) 'Emergence of potential biomarkers of response to anti-angiogenic anti-tumour agents.'. Wiley-Blackwell International Journal of Cancer, United States: 127 (6), pp. 1251-1258.

    Abstract

    Anti-angiogenic agents targeting tumour vasculature have an established place in clinical practice, and new data are constantly emerging. However, despite rapid clinical uptake, a very large number of questions regarding these agents remain unanswered. One of the main hurdles in clinical practice is lack of accurate and feasible ways of assessing response to drug beyond tumour reduction on conventional imaging. This review summarises recent developments in the field of biomarkers of response to anti-VEGF drugs.

  • Lunt C, Barber N, Montgomery A, Kalsi V, Parker T, Michael A, Pandha H, Hindley R. (2010) 'CYTOREDUCTIVE NEPHRECTOMY IN THE TYROKINASE INHIBITOR ERA'. MARY ANN LIEBERT INC J ENDOUROL, 24, pp. A303-A303.
  • Morgan R, Plowright L, Harrington KJ, Michael A, Pandha HS. (2010) 'Targeting HOX and PBX transcription factors in ovarian cancer'. BIOMED CENTRAL LTD BMC CANCER, 10 Article number ARTN 89
  • Michael A, John J, Meyer B, Pandha H. (2010) 'Activation and Genetic Modification of Human Monocyte-Derived Dendritic Cells using Attenuated Salmonella typhimurium'. THESCIENTIFICWORLD LTD THESCIENTIFICWORLDJOURNAL, 10, pp. 393-401.
  • Michael A, Syrigos K, Pandha H. (2009) 'Prostate cancer chemotherapy in the era of targeted therapy'. NATURE PUBLISHING GROUP PROSTATE CANCER AND PROSTATIC DISEASES, 12 (1), pp. 13-16.
  • Michael A, Politi E, Havranek E, Corbishley C, Karapanagiotou L, Anderson C, Relph K, Syrigos KN, Pandha H. (2007) 'Prognostic significance of erythropoietin expression in human renal cell carcinoma.'. BJU Int, England: 100 (2), pp. 291-294.

    Abstract

    To investigate, in a retrospective study, the expression of erythropoietin (Epo) in human renal cell carcinoma (RCC) and its correlation with overall survival, as Epo (an haematopoietic cytokine that regulates the production of red blood cells), with its receptor, was recently localized in non-haematopoietic tissues, e.g. liver, uterus, central nervous system, vascular endothelial cells and solid tumours.

  • Michael A, Hedayati B, Dalgleish AG. (2007) 'Disease regression in malignant melanoma: Spontaneous resolution or a result of treatment with antioxidants, green tea, and pineapple cores? A case report'. SAGE PUBLICATIONS INC INTEGR CANCER THER, 6 (1), pp. 77-79.
  • Michael A, Hill M, Maraveyas A, Dalgleish A, Lofts F. (2007) '13-cis-Retinoic Acid in Combination with Gemcitabine in the Treatment of Locally Advanced and Metastatic Pancreatic Cancer - Report of a Pilot Phase II Study'. W B Saunders Clinical Oncology, 19 (2), pp. 150-153.

    Abstract

    Aims: Adenocarcinoma of the pancreas is a cancer with extremely poor prognosis and limited therapeutic options. Retinoids are derivatives of vitamin A involved in the control of many biological functions, including cell growth and differentiation and the induction of apoptosis. On the basis of pre-clinical evidence and some clinical data, we conducted a phase II study of 13-cis-retinoic acid (13-cis-RA) in combination with gemcitabine in patients with unresectable pancreatic carcinoma. Materials and methods: Patients with histologically confirmed unresectable pancreatic carcinoma were treated with gemcitabine 1000 mg/m2 on days 8, 15, 22 plus 13-cis-RA 1 mg/kg on days 1e14 for six cycles. The end points included the objective response rate and median survival. Results: Thirty patients were recruited, 15 men and 15 women; 20 patients were evaluable. The median age was 65 years (range 44e79 years) and the median Karnofsky performance status was 80% (range 60e100%). The median followup was 21 months. One patient achieved a partial remission, seven patients had stable disease and 12 patients developed progressive disease. Toxicity was mainly haematological, with eight cases of grade 3 and four cases of grade 4 neutropenia, thrombocytopenia and anaemia. The median survival was 7.8 months (range 2.6e21.6 months). Conclusions: The combination of gemcitabine and 13-cis-RA was well tolerated, but we did not see improvement in the response rate. Further studies with other retinoids may be beneficial to patients with unresectable pancreatic cancer.

  • Hu JCC, Coffin RS, Davis CJ, Graham NJ, Groves N, Guest PJ, Harrington KJ, James ND, Love CA, McNeish I, Medley LC, Michael A, Nutting CM, Pandha HS, Shorrock CA, Simpson J, Steiner J, Steven NM, Wright D, Coombes RC. (2006) 'A phase I study of OncoVEX(GM-CSF), a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, 12 (22), pp. 6737-6747.
  • Michael A, Ball G, Quatan N, Wushishi F, Russell N, Whelan J, Chakraborty P, Leader D, Whelan M, Pandha H. (2005) 'Delayed disease progression after allogeneic cell vaccination in hormone-resistant prostate cancer and correlation with immunologic variables'. Clin Cancer Res, 11 (12), pp. 4469-4478.

    Abstract

    PURPOSE: There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. EXPERIMENTAL DESIGN: We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guerin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture. RESULTS: Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2). CONCLUSIONS: Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.

  • Michael A, Maravcyas A, Hill M, Wasan H, Lofts F. (2001) 'Preliminary results of phase I/II study to investigate the use of gemcitabine in combination with ralitrexed in locally advanced or metastatic adenocarcinoma of the pancreas'. CHURCHILL LIVINGSTONE BRITISH JOURNAL OF CANCER, 85, pp. 55-55.

Conference papers

  • Kelly Z, Pandha H, Madhuri K, Morgan R, Michael A. (2012) 'HOX GENE EXPRESSION IN OVARIAN CANCER'. OXFORD UNIV PRESS ANNALS OF ONCOLOGY, Vienna, AUSTRIA: 37th Congress of the European-Society-for-Medical-Oncology (ESMO) 23, pp. 68-68.
  • Kelly Z, Pandha H, Morgan R, Michael A. (2012) 'HXR9 AND PARP INHIBITION -A NOVEL THERAPEUTIC IN OVARIAN CANCER'. OXFORD UNIV PRESS ANNALS OF ONCOLOGY, Vienna, AUSTRIA: 37th Congress of the European-Society-for-Medical-Oncology (ESMO) 23, pp. 325-325.
  • McGrath S, Annels NE, Madhuri TK, Haagsma B, Larbi ED, Pandha HS, Michael A. (2012) 'Engrailed protein: A cancer-specific marker in epithelial ovarian cancer'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, Chicago, IL: 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) 30 (15)
  • Gungor H, Saleem A, Agarwal R, Blagden S, Michael A, Stronach EA, Chen M, Pickford E, Rama NR, Lewis YL, Carme SC, Salinas C, Smith DA, Krachey E, Santiago-Walker A, Gunn RN, El-Bahrawy M, Babar, SA, Morris R, Gabra H. (2011) 'Pharmacokinetic (PK)/pharmacodynamic (PD) analysis of escalating repeat doses of the AKT inhibitor GSK2141795 (GSK795) in patients (pts) with ovarian cancer.'. J Clin Oncol 29: 2011 (suppl; abstr 5064), Chicago USA: ASCO

    Abstract

    Background: GSK795 is a potent, ATP-competitive, pan AKT inhibitor. The purpose of this study was to characterize the relationship between AKT inhibition by GSK795 and downstream effects in platinum resistant ovarian cancer pts. Methods: Pts with recurrent platinum-resistant ovarian cancer received 25, 50 or 75mg of oral GSK795 daily. Dynamic FDG-PET scans and paired tumor biopsies (PTB) were performed prior to first dose and at 2 and/or 4 weeks post treatment. Semi-quantitative (SUV) and quantitative (Ki, MRglu) PET PD parameters were derived. PTB were analyzed by immunohistochemistry (IHC) for PD marker expression. PK samples were obtained in parallel. Response was monitored by RECIST and CA125 criteria. Results: 12 pts have been treated on study: 4 at 25mg, 4 at 50mg and 4 at 75mg. After completion of the 2 or 4 week post-treatment PD assessment, all eligible pts underwent intra-subject dose escalation to 75mg. The most common drug-related adverse events (≥ 10%) were decreased appetite (18%) and vomiting (18%), all G1/2. Mean Cmax and AUC24 increased with increasing doses and increased 1.2-fold from Week 2 to Week 4 where 2 and 4 week doses were the same. Median Tmax was 4 h. Overall tumor FDG metabolism decreased in 71% of tumors with treatment, although inter- and intra-patient variability in tumor uptake measurements following therapy was seen. There was no clear temporal or dose-response effect in FDG uptake. IHC analysis of PTB from 5 pts dosed at either 50 or75mg indicated that pAKT levels increased in 2/2 pts dosed at 75mg, pPRAS40 levels decreased in 4/5 pts, and Ki67 levels decreased in 4/5 pts after treatment with GSK795. 8/12 pts had stable disease and 4/12 had progressive disease by RECIST criteria at week 4. Currently 4 pts are still on the study, 2 > 24 weeks, with tumor regressions of 26% and 11% and CA125 decreases of 70% and 58% respectively. Conclusions: A dose response relationship between changes in FDG-PET and GSK795 was not observed in pts dosed from 25 to 75mg daily. Evidence of AKT pathway inhibition was observed in PTB from pts dosed with 50 or 75mg GSK795. Clinical activity evidenced by tumor regressions and CA125 decreases was also observed.

  • Michael A, Riley, C, Bokaee S, Denyer M, Pandha H, Annels N. (2011) 'EN2: A candidate antigen for the development of targeted therapies in ovarian cancer.'. JCO, Chicago: ASCO (J Clin Oncol 29: 2011 (suppl; abstr e15528))

    Abstract

    Background: Ovarian cancer remains the most lethal gynaecologic tumour in the Western world. Stimulation of the immune system to consolidate response to chemotherapy can potentially be beneficial however so far none of the vaccination strategies have offered survival advantage. Thus identifying and targeting clinically relevant antigens for immunotherapy continues to be an important research strategy. We have evaluated Engrailed-2 (EN2) as a potential target for vaccine strategy. EN2 is a homeodomain-containing transcription factor with a multifunctional role in neural development. There is evidence that over-expression of EN2 protein maybe linked to tumour development. Methods: Ovarian cancer cell lines were analysed by FACS for EN2 cell surface expression. EN2 expression in ovarian cancer tissue arrays were done by immunohistochemistry. A serum analysis (ELISA) was done to evaluate the presence of antibodies to EN2 in ovarian cancer patients and age-matched controls. A set of potentially immunogenic HLA-A2 restricted epitopes from the EN2 protein was identified using a computer algorithm SYFPEITHI. These peptides have been tested on HLA-A2 positive ovarian cancer patients’ PBMC using an in vitro culture method. The specificity of these T cell lines was analysed against T2 target cells loaded with or without EN2 peptides Results: Cell surface expression of EN2 was observed in ovarian cancer cell lines OVCAR3, OV90, CaOV-3, ES-2 and SKOV-3 of which ES-2 and SKOV3 showed strong expression. EN2 was also present in approximately 80% of ovarian cancer tissues whereas EN-2 expression was very low (<10%) or absent in normal tissues. Out of the 67 ovarian cancer patients 20.9% (14/67) had antibodies against EN2 compared to 2.4% (1/42) of age-matched female controls. 4 of the identified EN2 epitopes were able to generate peptide specific cytotoxic T lymphocytes in the ovarian cancer patients tested. Conclusions: The over-expression and immunogenicity of EN2 in ovarian cancer makes it a credible antigen to exploit as a novel target for ovarian cancer immunotherapy. ž

  • Coward JIG, Larbi ED, Pandha H, Michael A. (2011) 'The effect of age on first-line sunitinib treatment in patients with renal cell carcinoma (RCC).'. J Clin Oncol 29: 2011 (suppl; abstr e15096), Chicago USA: ASCO

    Abstract

    Background: Sunitinib is a first line treatment for majority of patients with metastatic RCC. The recommended dose of 50mg often results in a spectrum of serious side effects which subsequently lead to dose reduction and may have an impact on response rates. Methods: We conducted a retrospective analysis of 62 RCC patients from single institution treated with sunitinib between September 2007-May 2010. Patients were stratified according to age groups, into ≤ 70 year old (y.o.) and > 70 y.o. to compare tolerability, response rates and median survival. Results: All patients were evaluable for toxicity, 55 patients were evaluable for response. 38 (61.2%) were ≤ 70 y.o. and 24 (38.8%) were >70y.o. 2 patients (5%) of ≤70 and 5 (20%) of > 70y.o. were non-evaluable for response due to early treatment discontinuation. The response rate was 36% in ≤70y.o. and 21% in >70 y.o., stable disease (SD) was observed in 41% ≤70 y.o. vs 47% in the older age group and progressive disease PD:22% vs 31.5% respectively. 24 (38.7%) of patients required dose reductions after the first or second cycle- 12 (33%) in ≤70 vs 11 (59%) in >70 yrs old. A small number of patients presented with PS 2 and these were started on a reduced dose of 37.5mg: 3 (8%) in ≤70y.o. and 11 (58%) > 70y.o. Toxcities were comparable in both groups however grade 3 palmar-plantar erythema (PPE) and mucositis (18% vs 1.6% and 18 vs 8% respectively) were more prevalent in the younger cohort. Grade 3 diarrhoea and fatigue were more common in older patients (10% in >70y.o vs 1.6% in ≤70y.o. and 16% vs 9.6% respectively). Median survival was 23 months for both age groups. Conclusions: Elderly patients more commonly require dose reduction due to poor performance status and toxicity profile. The objective response rate is lower with the lower dose intensity however the rate of disease stabilisation is comparable in both groups. The lower dose of Sunitinib is well tolerated in the elderly and this regimen should be considered for older patients with poor performance status.

  • Michael A, Zylstra J, Pandha H. (2011) 'The sun study-a biobank of sequential blood samples from patients with prostate cancer'. WILEY-BLACKWELL BRITISH JOURNAL OF SURGERY, Royal Coll Surgery, Dublin, IRELAND: Annual Meeting of the Society-of-Academic-and-Research-Surgery 98, pp. 50-50.
  • Larbi E, Madhuri TK, Essapen S, Michael A. (2010) 'The impact of age on first-line chemotherapy treatment of epithelial ovarian cancer and primary peritoneal carcinoma'. Chicago USA: ASCO (J Clin Oncol 28:15s, 2010 (suppl; abstr 5118))

    Abstract

    Background: Standard treatment for epithelial ovarian (EOC) and primary peritoneal (PP) cancer is combination of surgery and chemotherapy. Most commonly used first-line drugs are carboplatin and paclitaxel (C/P). Treatment decisions involving elderly patients are complex and single agent carboplatin (C) is often preferred. To help the decision process we analysed the toxicity profile and outcome for elderly patients treated first line with both: C/P and C alone. Methods: A retrospective analysis of 82 elderly patients (> 75 years) treated for EOC and PP cancer between April 1996 and October 2009 was performed. Age, comorbidities, CA-125 at diagnosis, histology, stage, outcome of cytoreductive surgery (CRS), chemotherapy regimen, toxicity and clinical response were recorded. Results: The majority, 76% (63/82) of patients had serous ovarian cancer with 58.5% presenting as FIGO stage 3c, median CA-125 of 340.2 U/mL (range: 5-5702). 67.1% (55/82) had CRS with 61.9% (34) optimally debulked. 84.2% of patients (69/82) received chemotherapy and were therefore evaluable for the purpose of this analysis. 94.2% (65/69) completed treatment (mean number of cycles = 5.1). 35.4% (23/65) received C/P and 63.1% (41/65) received single agent C. The commonest complication was peripheral neuropathy- 56.5% (13/23) in combination arm. Treatment was deferred mainly due to haematological toxicity: neutropaenia - 13.9% (6/43) in the C arm and 11.1% (3/27) in C/P; grade 3/4 thrombocytopaenia-4 (3-C, 1-P/C); grade 3-anaemia-1 (C). Dose reduction was required for 46.1% (12/26) in the combination arm and 25.5% (11/43) in the C arm. There were 35 dose delays-34.6% (9/26) C/P and 60.4% (26/43) C. Median survival for this group of patients was 21.3months. Median PFS was 8.8 months in C/P arm and 7 months in the C arm (95% CI-0.71 to1.8-not statistically significant). Conclusions: The toxicity of combination treatment with C/P is comparable to single agent C in elderly population with frequent dose delays and dose reductions. Initial assessment of comorbidities and performance status is essential however effort should be made to offer patients optimal treatment with the combination regimen.

  • Michael A, Plowright L, Boxall A, Bhatt A, Di Palma S, Parker C, Pandha H. (2010) 'Evaluation of EN2 as a urine-based biomarker for prostate cancer.'. J Clin Oncol 28, 2010 (suppl; abstr e15129), Chicago USA: ASCO

    Abstract

    Background: Prostate cancer is a leading cause of cancer related death in men but its diagnosis is still complicated by the lack of a highly predictive biochemical marker. Here we show that the transcription factor Engrailed-2 is secreted from prostate tumours in a highly specific manner and is present in the urine of men with prostate cancer. Methods: Urine was collected under standardised conditions from men with prostate cancer, or with non-cancerous conditions of the prostate such as benign prostatic hypertrophy, or men who were found to have no prostate abnormalities after saturation biopsy. Results: Engrailed-2 protein was detected in the untreated, unconcentrated urine of 62% of men with prostate cancer, but only 3% of men with no prostatic abnormalities (n=258, p<0.001). Conclusions: Thus Engrailed-2 is a potential diagnostic marker for prostate cancer.

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