ProfSupratik Basu

1. Myeloma and Micro environtment
2. Lymphoma
3. Drug developement in Myeloma( Ongoing Reserach with University of Wolverhampton)


OUTLINE OF ONGOING RESEARCH PROJECTS and GRANTS



A .University of Birmingham


Myeloma Research Document
At the University of Birmingham in collaboration with Royal Wolverhampton Hospitals, there are a significant number of research projects ongoing that rely on the primary samples arising from the Royal Wolverhampton NHS Foundation Trust, mainly focusing around the changes in metabolism of the bone marrow during the pathogenesis of multiple myeloma, and the implications of this altered environment on the ability of the body to appropriately clear the disease.
The Tennant research group focuses on the metabolism of the bone marrow microenvironment during the onset and pathogenesis of multiple myeloma. They are currently focusing on three research themes; the role of loss of the metabolic enzyme SUCLA2 (succinyl coA ligase A2) as a passenger mutation in malignant plasma cells, how upregulation of PADI2 in the bone marrow mesenchymal stem cells supports tumour growth, and the metabolic cooperativity between the stromal cells and malignant plasma cells. The first is currently in preparation for grant funding, the second is funded by Cancer Research UK, and the last is also under development for grant funding.
The role of SUCLA2 is currently unknown, but it is lost in the majority of the 40% of all multiple myeloma patients who have loss of the retinoblastoma tumour suppressor (RB1) protein. We are currently profiling what metabolic changes occur in myeloma cells that have lost this central metabolic enzyme, as we believe that it will result in a vulnerability in their metabolism that could be therapeutically targeted by novel inhibitors.
The bone marrow stroma of MM is known to be critical in supporting disease pathogenesis. However, the interactions that drive this are unclear. We recently described the increased expression of peptidyl arginine deiminase 2 (PADI2) in bone marrow mesenchymal stem cells (BMMSCs) of MM patients, and its role in supporting chemotherapy resistance in myeloma cancer cells. We showed that upregulation of PADI2 directly increased interleukin-6 (IL-6) production by BMMSCs through the citrullination of histone H3 arginine 26 (H3R26cit) in its promoter region, resulting in resistance to the first-line therapy, bortezomib. Therapeutic targeting of this enzyme may therefore greatly improve therapy responsiveness in MM patients.
Finally, we are examining the metabolic interplay between the mesenchymal stem cell and myeloma cell in the bone marrow – the metabolites each use, and how they share them between each other. As we know that myeloma cells require bone marrow localisation for their proliferation and other malignant phenotypes, it is possible that the metabolic support of the stroma is critical for this – interrupting the relationship between the two cell types may increase efficacy of current therapies. This research strand directly links with that of Dr. Sarah Dimeloe.
Dr. Dimeloe holds a John Goldman Fellowship from Leuka to investigate the effect of changes in the myeloma metabolic microenvironment on the ability of T cells to appropriately kill tumour cells. This is a critical study, given the new drugs coming to the clinic that rely on having a functional T cell immune response. The role of T lymphocytes in the MM bone marrow (BM) and, reciprocally, how the MM BM microenvironment impacts T cell function are poorly understood. T cell function is inextricably linked to their metabolism and BM metabolic features are markedly altered in MM. This fellowship proposes a step-change in the understanding of T cells in MM, by performing high-resolution analyses of BM T cell metabolism, coupled to assessment of immune function, across the spectrum of this disease. Furthermore, metabolic and immune cross-talk between key BM cell types and T cells will be mechanistically interrogated, together with the implications for immune function. Finally, based on these data, T cells with optimal metabolic traits for survival, function and MM eradication in the BM microenvironment will be generated using established pharmacological and genetic approaches.




B. University of Wolverhampton ( Phd Studentship, with Prof Weiguang)


1 Project Title:
Using Imuthiol to target hypoxia-NFkappaB-CSCs pathway and improve the treatment outcomes of multiple myeloma treatment

2 Detailed information about the project

2.1 Abstract of the proposed investigation
Background: The prognosis for patients with multiple myeloma (MM) remains challenging. Our pilot studies demonstrated that Imuthiol is highly toxic to cancer stem cells. Imuthiol has been intravenously used in clinical trials with excellent safety record. The success of this study may lead to quick translation of Imuthiol into MM treatment.

2.2 Background and clinical relevance of the project
Recent novel therapy and immunotherapy in MM have improved outcome and survival but come with an increasing cost burden which has major health economic ramification. Current best therapeutic options involve combining a proteasome/NFkB inhibitor with an iMId (lenalidamide or thalidomide) for upfront and relapsed disease. However the cost burden of this combination has become prohibitive even for developed nations. Imuthiol could be an ideal affordable potent NFKB inhibitor to study as a single agent as well as in combination with other immunomodulators in myeloma. This may lead to potential combination therapies which will be very effective as well as affordable.

2.3 Relevance of the project to the health needs of the Black country

New Cross Hospital is one of the largest Myeloma trial centres in UK. It is a Clinical Trial Network Site of Myeloma UK. It recruits consistently to large academic and Industry studies globally. The patient base largely consists of local population as well as referrals from other areas of West Midlands, including Birmingham and Warwickshire. This project potentially can lead to therapeutic advances in myeloma therapy which may lead to affordable treatment for this still incurable cancer. This has significant implication for NHS therapeutic costs




C. University of Manchester( Manchester Royal Infirmiry, Dr A. Rocci)


Background and aims:
Multiple myeloma (MM) is a blood cancer diagnosed in almost 6,000 new patients per year in the UK. Although median overall survival has improved significantly over the past 15 years, around 30% of patients die within 1year of diagnosis. The high mortality is largely due to late diagnosis when the disease is advanced and treatments less effective. The symptoms of MM are non-specific and difficult to interpret hence over half of patients require 3 or more consultations with their GP before being referred to a haematologist. This results in considerable delay in diagnosis, which in many patients occurs only after
attending A&E with life-threatening complications ofadvanced MM. Diagnosis after A&E attendance is associated with high cost and poor outcomes. The 1-year survival for such patients is just 51% compared to 82% for patients diagnosed via GP referrals. The use of policies, guidelines and flowcharts has been trialled to improve the diagnosis of MM. However, these have not yielded any clear benefits, and in some cases
further delay MM diagnosis. In contrast to other cancers, 99% of patients with MM have one or more serum markers (paraprotein and/or abnormal free light chains) that can allow diagnosis
without requiring invasive procedures (i.e. biopsy) or radiological tests. However, a challenge is that these 3 serum markers are also present in patients with a
largely benign pre-MM condition called monoclonal
gammopathy of undetermined significance (MGUS). The prevalence of MGUS is around 7% of the general population above the age of 70 (approximately 400,000 people in UK), and with an aging population the option of referring all these patients to haematologists in secondary care is not viable. New approaches are needed to differentiate patients with MM, who need
urgent review by a haematologist, from those with MGUS, who require regular follow-up with their GPs but no active treatment.
The aims of this project are:
1) To develop a noninvasive risk scoring algorithm to differentiate patients
with MM from those with MGUS;

2) To validate the performance of the algorithm in an independent cohort

3) To pave the way towards a feasible and innovative approach in the management of patients
with MGUS, which will involve use of the algorithm in primary and secondary care.

Patient dataset:
Fully anonymised data from patients with MM or MGUS currently treated or followed-up at MRI will be used to develop a risk scoring algorithm able to differentiate these two conditions. Few parameters are expected to be independent predictors of MM on their own but the combination of multiple variables in the scoring system is expected to increase accuracy of the
algorithm. Hence, we will collect data for age, gender, ethnicity, haemoglobin, creatinine, adjusted calcium, paraprotein (type and quantity), albumin, serum free light chain kappa and lambda, urine protein/creatinine ratio, and Bence Jones proteinuria from 400 patients with MGUS and 400 patients with MM at MRI (learning series). The algorithm will be developed, as described below, and validated in an independent cohort of 400
MGUS and 400 MM patients from the Wolverhampton area (validation series).


D. Collaboration with Oxford and Southampton

Collaborative work was undertaken with Oxford and Southampton to understand the role of Salvage chemotherapy in refractory myeloma( VTDPACE). UK experience with 70 patients were reported. The work has been accepted for presentation EHA 2019( European Haematology Association International Meeting in, Amsterdam June 2019

E. Collaborative work with CELGENE( International)
Effect of combination therapy with Pomalidamide with or without prior Immunotherapy exposure with Anti CD38 antibody exposure and Clarythromycin( Project being planned and instigated by CELGENE to be led from Royal Wolverhampton Hospital. Collaborative hospitals will be from Birmingham, Southampton and Oxford



F. Collaborative work with Binding Site

Project to study the cause and rout to late diagnosis in Myeloma in Acute Hospital setting. Data and project running in Collaboration with Binding site international. This will possibly identify certain test parameters from primary care setting which can avoid late diagnosis in Myeloma( Identified problem in National Cancer Intelligence Report (www.ncin.org.uk/databriefings)

F. Collaborative work with Birmingham Hospitals and UCL

Prospective data analysis on effect of split dose and once weekly Velcade and Daratumamab in relapsed Myeloma: This method of delivery is unique to UK. Collaborative analysis will be done within Black Country , University College London Hospitals and Birmingham

Current Role and Responsibility
1. Clinical Research Lead for Haematology and Oncology ( DIV1) , CRN, NIHR West Midlands


2. Haematology Research Lead for West Midlands Clinical Research Network.

3. Chief Investigator for UK for International MAIA Trial studying the role of Immunotherapy in combination with Immunomodulators in Non Transplant eligible myeloma patients


4. Principle Investigator for more than 40 international and NCRN Trials including Myeloma IX, XI, XII


5. Translational Research, University of Birmingham.

6. CI of NIHR Combilite Trial in AMU setting( Completed)

7. PI of more than 40 CRN/ Industry Phase II and III international studie

8. Member of NCRI Myeloma Subgroup

9. TYA lead for Trust


10. Coordinating Collaborative Research ongoing with University of Birmingham, Oxford, Manchester University and Southampton for Publication and Trials

GRANTS:
Research Grant:
1 .CRUK Grant 2008 ( University Birmingham): The Role of Marrow Fibrobast as a determinant Tumour Cell survival in Myeloma £150,000

2 Back pain prevention in multiple myeloma using an external spinal brace -
a feasiblity study ( NCRI Grant with University Hospitals of North
Midlands NHS Trust and Royal Wolverhampton NHS Trust) 2015 £125,000

3. CRUK Small molecules (PADI2) in Myeloma Grant Awarded June 2017( Co application with University of Birmingham) £150,000

4. John Goldman Fellowship( With UHB) Awarded 2018
“Defining T cell metabolic fitness in the myeloma bone marrow” £124,852.19



5. Development Of a predictive Model to Identify patients with Multiple Myeloma among those having MGUS (DOMINUS Project) Co application with University of Manchester