— The Josh Carrick Foundation

Robert Huddart

Prof Robert Huddart

The Platinum study

Background

Testicular cancer is the most common cancer in young adults aged between 14-44 years. Chemotherapy based on a drug called cisplatinum based regimens have resulted in dramatic improvements in cure rates.

The good news of this is that most men with testicular will be cured. But this comes at a cost and over the last two decades, there has been increasing awareness of the risk longer term toxicities in survivors.

Multiple studies, including work at Royal Marsden have demonstrated increased risk of cardiovascular (heart disease) disease  in testicular cancer survivors. Various factors such as mediastinal radiotherapy, cumulative cisplatin dose have been implicated (Huddart et al 2003) Furthermore, testicular cancer survivors are at a higher risk (nearly 2-fold) of metabolic syndrome, a constellation of cardiovascular risk factors which has been demonstrated to increase the risk of cardiovascular disease by twofold and diabetes by fivefold in the general population.

The other toxicities which have been studied in testicular cancer survivors include lung, kidney and testicular problems and those of the nervous system (nerve and hearing damage).

More recently, there has been a growing interest to modulate the risk of late- effects of treatment in survivors. In particular why some people develop problems and others don’t. Some people may have genes that may increase the risk of side effects an area or research called ‘ pharmaco-genomics’.  Work in this area is limited in testicular cancer is limited however some groups have studied neurotoxicity [Glutathione-S-transferase (GSTP1)] , ototoxicity  (GSTM3, GSTP1), Megalin (LRP2), mitochondrial sequence variations) pulmonary function [Bleomycin hydrolase (BLMH)], and early relapse and overall survival (BLMH).

Aims of project

The primary aim of this proposal is to study factors leading to long term side effects in survivors, which compromise quality of life.

The primary objectives of this proposal are firstly to study molecular genetics of neurotoxicity and  ototoxicity after treatment (Glendenning et al  2010) as part of a large collaborative effort to investigate the causes of toxicity by investigating pharmacogenomics interactions led by the National Cancer Institute in the US (U.S. National Cancer Institute funded study 1 R01 CA157823-01A1: Genetic Variants and Biomarkers of Platinum-related Toxicities CI Dr Lois Travers).

DNA samples collected in this study will also be used to validate the frequency of the G/G genotype of BLMH, which has been reported to predict for earlier relapse and reduced survival and will also be added to the ICR/RMH database. Once collected and annotated they can then be a resource for future UK based research

What are we going to do?

This study is based at the Royal Marsden Hospital. We will invite men who have received chemotherapy at the Royal Marsden to take part. Our target is to recruit 400-600 men who have been treated over the last 20 years. Most will be on follow up but some will be invited back after discharge. They will be asked to complete a questionnaire about their background and current health, supply and blood test and undergo a hearing test. Most of the samples will be shipped for analysis in the US but some will kept at the Institute of Cancer Research for future research.

The samples will be analysed to look for differences in the genes of those with and with out problems. The questionaires and details of treatment will be analysed to to see if this gives clues as to who will or won’t get problems.

Current status

With the support of the Josh Carrick foundation we have secured full funding to run this study. We are currently in the final stages of the complex set up of the study, awaiting for final agreement on contracts between RMH/ICR and Indiana University.

We are holding interviews for a data manager to run the study in early December and hope to start soon afterwards!

Prof Robert Huddart, November 2015

Dr Erik Sahai

The Josh Carrick Foundation is proud to support Dr Erik Sahai’s work at the London Research Institute. We have already donated £40,000 to Erik’s research team, who are using cutting edge technology to tackle metastasis – the spread of cancer.

“On behalf of my team, I would like to extend a huge thank you to Josh Carrick Foundation for their donation towards funding the work of my laboratory. Your support is helping us to continue our vital research, which is focused on a better understanding why cancer spreads and why existing therapies sometimes fail. This information will enable us to better understand how we might target the spread of cancer with existing drugs, and how we can design new ways to ensure that cancer therapies do not fail.” – Dr Erik Sahai

Here’s a more detailed look at his work…

Stopping cancer spread in its tracks

The ability to spread around the body is one of the most deadly properties of cancer cells – in fact, most deaths from cancer are caused by the disease spreading. Dr Erik Sahai at Cancer Research UK’s London Research Institute is probing the inner secrets of cancer cells and their environment, uncovering how they move and seeking out new treatments to tackle the problem.

Unravelling complex biology

A tumour isn’t just a collection of cancer cells. It’s part of an ecosystem made up of many other components – called the ‘microenvironment’. Cells from the body’s immune system, chemical signals and blood vessels that deliver nutrients exist side by side with cancer cells, and all play a part in cancer spread.

Scientists in Dr Sahai’s lab are working to understand a type of cell in the tumour microenvironment called a cancer-associated fibroblast (CAF). CAFs help cancer cells spread, by burrowing through the tissue around a tumour and creating ‘tracks’ that cancer cells can move along.

By studying CAFs in the lab, Dr Sahai’s team have worked out how cancer cells reprogram healthy cells around the tumour so they become CAFs. Understanding this complex biology could help researchers design new treatments to target CAFs, so they can no longer aid cancer spread.

A view to a kill – high-tech imaging

Dr Sahai’s team are also using new imaging techniques to watch cancer cells in action. They can see what is happening in living tissue in a stunning amount of detail – shedding light on how cells send messages to each other.

The researchers are using this technology to understand how different treatments affect cancer cells, and how cells that have spread can actually resist some cancer drugs. Their aim is to improve treatment by finding the best way to disable spreading cancer cells.

Modelling cancer spread

Dr Sahai and his colleagues have also developed computer models that predict how cancer cells move in different environments.  These models could help to virtually ‘test’ new and improved treatments by predicting the effects of disrupting different types of cell movement.

The researchers hope their models will help find a way to lock the cancer cells in place, to make it easier to destroy them.

Read the latest project update from Dr Eric Sahai here.


Professor Gordon Rustin

The Josh Carrick Foundation is also proud to be able to support Professor Gordon Rustin’s research. Prof Rustin is the lead clinician for testicular cancer at the Mount Vernon Cancer Centre.

Not only did Josh receive a high standard of care at Mount Vernon under Professor Rustin’s care, Professor Rustin is highly regarded within his profession. He was made director of Medical Oncology at Mount Vernon Hospital in 1995, was awarded Honorary Professorship by UCL in 2001 and in 2011, was made Professor of Cancer Therapy at the Institute of Cancer Research.

He has published over 300 papers on management of gynaecological cancers and germ cell tumors, the use of tumor markers, especially CA 125, and on phase I, II and III trials. Furthermore, he has led the world by introducing functional imaging as a tool to determine the activity of vascular disrupting agents.

Prof Rustin’s work in his own words…

“I am extremely grateful to the Josh Carrick Foundation for helping to fund the clinical trials I am conducting. Just over half of the patients with cancer of the testicle have a type of cancer called seminoma. The standard chemotherapy given to patients whose cancer has spread has been a combination of Bleomycin, Etoposide and Platinum called BEP. Although this chemotherapy can cure over 90% of patients even with advanced disease, it has many side effects, some of them long lasting and most patients require admission to hospital for up to 15 days in order to receive treatment.  This can be distressing for both the patient and their families.

Since 2004, over 100 selected patients with advanced seminoma at St Bartholomew’s and Mount Vernon Hospitals have been treated with 3-4 infusions of a very high dose of just one drug called Carboplatin. The preliminary finding is that Carboplatin appears to be at least as effective as BEP, but has far fewer side effects. Furthermore, the chemotherapy is given in  just over 1 hour so patients can avoid hospital admission.

Many patients treated with Carboplatin have quite large lumps of cancer usually in lymph nodes at the back of the abdomen. These lumps often shrink quite slowly leaving patients with a residual mass, typically composed of scar tissue. PET-CT scans measure the metabolic activity of tumour masses and can give an indication as to whether a mass contains active cancer or just scar tissue. There is a good chance that doing serial PET-CT scans on these patients could help to determine how well the mass of seminoma is responding to therapy. Most importantly it could be used as a guide to whether patients require 3 or 4 courses of Carboplatin. Reducing the number of courses may help to minimise the side effects experienced by patients, therefore improving patient wellbeing and their experience of therapy. The scans can also help to determine whether any additional therapy is needed.

This trial has been set up to confirm that Carboplatin given at a high dose called AUC-10 is as effective as the initial results suggest and to clearly record all associated side effects. PET-CT scans will be used in this trial to help direct therapy. The NHS is prepared to fund an initial and end of treatment PET-CT scan but not the intervening scans as the additional scan is not considered to be standard care. We are therefore very grateful that the Josh Carrick Foundation has agreed to fund the expensive extra PET-CT scans.”