Our First Research project

Using DNA Repair Biomarkers to Predict the Response of Cancer Patients to Anticancer Therapy.

 

Dr. Christopher N. Parris

Senior Lecturer

Brunel Institute of Cancer Genetics and Pharmacogenomics

Division of Biosciences

Brunel University

Kingston Lane

Uxbridge

Middlesex, UB8 3PH

Tel: 01895 266293

christopher.parris@brunel.ac.uk

 

Cytotoxic (cell killing) therapy (chemotherapy and radiotherapy) are the main methods of anticancer therapy for the treatment of early stage (primary) cancers or those that have spread (metastasised) to other sites in the body. The effectiveness of anticancer therapy can be limited by the extent and severity of painful side-effects which are caused by the administration of the treatment. The painful side-effects associated with anticancer therapy can decrease patient welfare, leave the patient with persistent or permanent disabilities and increase patient care cost to the NHS.

            Cytotoxic anticancer therapy works by damaging and ultimately destroying the DNA within cancer cells. However, normal non-cancer cells within the body are also destroyed by the treatment and it is the extent of normal cell damage that will govern the level of side-effects experienced by the patient.

Most human cells have number of cellular DNA repair mechanisms that can reverse the effects of DNA damage and return the cell back to its normal condition. Therefore the efficiency of DNA repair in cancer and normal cells will play an important role in:

  1. Controlling tumour response and determining the clinical outcome (cure or non-cure of the cancer) by the anticancer therapy.

  2. Determining the severity of side-effects experienced by the patient.

Interestingly, some individuals are afflicted by inherited conditions where they have an inborn inability to repair certain types of DNA damage. Such individuals would be at extreme risk of life-threatening side-effects if they were treated with normal anticancer therapy. An example of such a disease is Ataxia Telangiectasia (A-T), in which there is an inability to repair DNA strand breaks caused by radiation exposure. These patients also have an elevated risk of cancer as a result of the disease but it would be lethal to the patient if their cancers were treated with radiotherapy and consequently other treatment options would have to be considered.

            While A-T is an extreme case, there is good evidence to suggest that cancer patients with more mild and previously undiagnosed defects in DNA repair mechanisms are also at risk of dramatic and painful side-effects during therapy. In fact our research group recently demonstrated in a patient whom experienced drastic side-effects to radiotherapy (eventually leading to death), a previously un-described defect in a gene controlling the repair of radiotherapy induced DNA damage (Abbaszadeh et al, 2010). Therefore a pre-treatment diagnostic test to determine how cancer patients respond to therapy is likely to prevent such occurrences in the future.

For many years, clinicians and scientists have looked to develop experimental methods that could be used to predict how cancer patients are likely to respond to anticancer therapy. All of these tests rely on taking a sample of tissue (normally a skin biopsy) from the cancer patient. These cells are then grown in culture and exposed to the very same drugs and/or radiation that a patient might receive during the course of the anticancer treatment. The response of the patient’s cells is compared to cells from a normal individual, and if the cancer patient’s cells are abnormally sensitive then it is likely that the patient may experience a high level of painful side-effects. Some of these methods can reliably predict how a patient might respond to therapy, however, the tests take many weeks to perform and therefore cannot provide a result within a useful timescale, since it is imperative to commence therapy as soon as possible following diagnosis. Thus there is a need to develop a simple diagnostic test that will provide useful information to the consulting oncologist within days rather than weeks enabling the design of an effective treatment protocol without delay.

            To address this problem our research group has been employing a new method as a predictive test. This method is called the gamma-H2AX assay. When cells are exposed to radiotherapy or anticancer drugs, a break (damage) in the DNA occurs. The cell responds to this damage by activating (phosphorylating) a protein bound to the DNA called H2A. Once this protein is activated it is now called gamma-H2AX and it acts as a “beacon” (foci) to attract the appropriate DNA repair protein to repair the DNA break. If the DNA damage is successfully repaired, the gamma-H2AX foci will disappear within a few hours. If there is a failure to repair (as would be expected in a patient with severe side-effects) then the gamma-H2AX foci will persist. It is possible to measure and quantify the level of gamma-H2AX foci within both cancer and normal cells from patients and this test can be performed within 24 hours.

How the test is performed

  1. 10 ml of blood is taken from the patient and delivered to the laboratory.
  2. The white (lymphocyte) cells are purified from whole blood.
  3. The lymphocytes are treated with radiotherapy or chemotherapeutic drugs to cause DNA damage.
  4. The measurement of gamma-H2AX foci is performed over the period of one day.
  5. Results are returned to the oncologist for consideration in designing an appropriate treatment schedule for the patient.

In collaboration with Dr Nick Plowman (Head of Radiotherapy Department) of St. Bartholomew’s Hospital, London, UK, we have recently demonstrated that a group of patients who had earlier experienced severe radiotherapy induced side-effects (including severe nerve damage, deep skin destruction and severe ulceration) during routine treatment were unable to repair radiotherapy-induced DNA damage. Lymphocyte cells were exposed to radiotherapy and failed to repair DNA strand breaks measured by gamma-H2AX levels. Therefore, we have preliminary exciting data using a rapid and convenient assay which suggests we can successfully predict how individual patients might respond to anticancer radiotherapy within the clinical setting.

 Experimental Plan

To fully exploit the potential of our diagnostic test we wish to extend these findings to:

  1. Analyse gamma-H2AX induction in human cells using a panel of cancer chemotherapeutic drugs with different mechanisms of action.
  2. Exploit our diagnostic test (gamma-H2AX assay) within the clinic to pre-determine painful side-effects in patients with genetic conditions which may leave them at risk of extreme toxicity to radiotherapy and/or chemotherapy.

We have demonstrated that we can use the gamma-H2AX test to predict how patients are likely to respond to radiotherapy. It is now important to take this technology to the next stage and place it within the clinical setting. Initially we aim to test specific groups of cancer patients with:

  • A strong family history of cancer, especially breast cancer, as evidence suggests that such patients might be hypersensitive to both radiotherapy and chemotherapy (Moule et al., 2009).
  • Potential DNA repair defects which may leave them at extreme risk during radiotherapy.
  • Unusual tumours or case histories where the consulting oncologist suspects that there may be an over-reaction to the treatment.

The long-term goal of this research is to provide a mechanism whereby anticancer therapy can be designed for each patient based upon our diagnostic test. Therapy can then be individualised and made more effective and tolerable for each patient.

In conclusion, we have good experimental evidence that using our DNA repair based test, we can identify patients at risk of severe side-effects during therapy. This data has been based upon retrospective studies. However, now we need to move the test forward into a clinical setting. We appreciate that this will take a few years to fully exploit the technology for patient benefit but require funding to perform further experiments towards this goal.

 

 

References

  1. Abbaszadeh F, Clingen PH, Arlett CF, Plowman PN, Bourton EC, Themis M, Makarov EM,  Newbold RF, Green MHL, Parris CN. A novel splice variant of the DNA-PKcs gene is associated with clinical and cellular radiosensitivity in a xeroderma pigmentosum patient. J.Med Genet. 2010, 47(3):176-181.
  2. Bourton EC, Plowman PN, Smith D, Arlett CF, Parris CN. Prolonged expression of the g-H2AX DNA repair biomarker correlates with excess acute and chronic toxicity from radiotherapy treatment. Int. J. Cancer 2011;129(12):2928-34.
  3. Bourton EC, Plowman PN, Adam Zahir S, Senguloglu GU, Serria H, Bottley G, Parris CN. Multispectral Imaging Flow Cytometry Reveals Distinct Frequencies of g-H2AX Foci in DNA Double Strand Break Repair Defective Human Cell Lines. Cytometry Part A, 2011, Dec 13. doi: 10.1002/cyto.a.21171. [Epub ahead of print].

Coventry’s Male mile.

Coventry City footballs club have organised a Male Mile at their Ricoh football Stadium for their Mens Health week. They have kindly offered to raise funds for us at the event and many of #teamnuts will be there to collect and offer morale support.

If you live in or near Coventry why not enter as a warm up to the Fathers day 5K event.

Competition winner!

Please meet our competition winner Donna Klander on our new poster. Donna entered our competition to send in a picture with a ball or balls covering you bits and pieces. Donna’s poster will be used nationwide to help raise awareness.

Thank you Donna and Congratulations!

Liam’s Story

Liam is a chap I have been speaking to for sometime on Twitter and he is a brilliantly strong and kind person, this is his story……..

Hi, my names Liam, I’m 14 years old and my grandad recently passed away from cancer. My grandad has always been a father figure to me as my real dad was never around. I’ve always been close to him, and in April 2009 I had a huge argument with my mum which forced me to move in with my nan and grandad who were kind enough to take me in despite them both suffering from health problems. My grandad has beat one type of cancer, two heart attacks and lived through a near fatal anuerysm, he had 25% kidney function for much of his later life. Then in September 2010 he was diagnosed with upper GI cancer which is for those of you who don’t know is cancer of the Esophagus which limited his ability to eat and drink even simple things such as; mousses, soft sponge cake etc. After Christmas of 2011 his health started to deterioate, in January his mobility was gone and he had to stay in bed so instead of him being upstairs all the time on his own we got a hospital bed put in downstairs so he could be with the family. A few days after my birthday which was on March the 3rd I was told by some family members that my grandad had 1-2 weeks to live, however a few days later he passed away on the 17th of March. I’ve never done anything harder than watching him die as it wasn’t just a grandad I was losing it was a dad, a bestfriend and most of all someone I could trust with anything. His funeral was on the 5th of April and luckily I had my best friend Louis there who was kind enough to come to support me, he also knew him. Well thats my story, hopefully nobody else has to die of this sick, sick disease.

Jack Thompson!!!!

UPDATE 19-5-12 Jack has successfully completed his jump and has raised a magnificent £370.00 for the charity.

“I would personally like to thank him on behalf of the charity. Thank you Jack you are a star” (Mark Bates Founder)

_______________________________________

21 year old Jack Thompson has decided to do a Parachute jump for us, Jack from Gornal in Dudley (a former pupil of Ellowes Hall) is now working as an engineer in Netherton.

Jack said “I hope to raise lots of money for the charity”  So if you want to support Jack and sponsor him, please get in touch through the website and we will pass your details on to him.

Jack will be doing his jump on Saturday the 3rd March at Hinton Skydiving

We wish Jack all the best and thank him for doing it for us.

We’re Registered!!

We are very proud to announce that we are now a fully registered Charity. After long hard weeks we managed to get through the process and we are very happy.

We would like to thank everyone associated with the very first race we had back in October who have worked so hard to raise the lions share for the £5000 needed to be able to register our charity. So lad’s you know who you are thank you!!!

We would also like to thank each and every one of #teamnuts who have bought a wristband, Pen, Trolley coin, Tee shirt or calendar because every penny counts and your contribution is as important as any other.

Please keep buying, keep fundraising and keep running for us!! We LOVE you all!!

Charity Number 1146185

Male Cancer incidence and Mortality rates

Below is a list of Male Cancer Incidence (shown as I) (recorded in 2008) and Mortality rate (Shown as M) (recorded in 2009). This is the reason we need your help. The incidence continues to grow as does the Mortality rate.

We need to put a stop to this and beat Cancer! Please do whatever you can to help or donate.

 

Bladder (I)7,390 (M) 3,352
Bone and Connective Tissue (I)1,281 (M) 549
Brain and Central Nervous System, Malignant and NonMalignant
(I) 4,602  (M) 2,621
Brain and Central Nervous System, Malignant  (I)2,062  (M) 2,179
Brain and Central Nervous System, Non-Malignant
(I) 1,879 (M) 442
Breast (I) 341  (M)77
Cancer of Unknown Primary (I) 5,028 (M) 4,962
Colorectum (includes Anus)(I) 22,097 (M) 8,600
Colon  (I)13,359  (M) 5,076
Rectum, Rectosigmoid Junction and Anus  (I) 8,738  (M) 3,524
Hodgkin Lymphoma (I) 948 (M) 171
Kidney (I) 5,377 (M) 2,296
Larynx (I) 1,890 (M) 650
Leukaemia (I) 4,463 (M)2,557
Acute Lymphoblastic Leukaemia (I) 369  (M)129 1
Acute Myeloid Leukaemia  (I) 1,303  (M)1,311
Chronic Lymphocytic Leukaemia  (I) 1,703  (M) 669
Chronic Myeloid Leukaemia (I) 339  (M) 111
Liver  (I) 2,286  (M) 2,159
Lung  (I) 22,846 (M) 19,724
Malignant Melanoma  (I) 5,584 (M) 1,159
Mesothelioma (I) 1,967  (M) 1,913
Multiple Myeloma (I)  2,480  (M) 1,367
Non-Hodgkin Lymphoma  (I) 6,343  (M) 2,423
Oesophagus (I) 5,461 (M) 5,097
Oral  (I) 3,824  (M)1,273
Other Digestive Organs (I) 362(M) 1,518
Pancreas (I) 4,001 (M) 3,881
Penis (I)  488 (M) 118
Prostate (I) 37,051 (M) 10,382
Small Intestine  (I) 576 (M) 213
Stomach (I)  4,923  (M) 3,167
Testis (I) 2,138 (M) 69
Thyroid  (I) 558 (M) 137

Spend Save Support!!

Spend Save and Support

We have teamed up with www.easyfundraising.org.uk so now you can save money shopping online and earn money for the charity.  There is no cost to you or the charity.

Easyfundraising is FREE to join and there are no subscription charges.  The website is an online shopping portal with access to 000’s of retailers offering discount codes, cashback and cash incentives.

Sign up at http://www.easyfundraising.org.uk/causes/ballstocancer/?t=Easyfundraising-lo&v=a&=  and start saving.

BTC 11 v Aston Villa Old Boys

18-01-12 We are pleased to say we have our first two members of the team to play against Villa in August. Other places will be available soon. Please keep watching for further updates.

We are very happy to announce that on the 5-8-12 our team will be playing against a team of Villa old boys. Our team will be made up of 16 men (over 30’s) places will be auctioned via our eBay site in the next few weeks.

So if you would like to be part of the team the keep an eye on the website and start bidding!!

The Villa players will stay behind in the bar after the game for a chat an autographs.

Our manager will be Jody Craddock

We will be selling tickets for spectators and friends and family to come and watch, we will also be looking for businesses to advertise on our programme for the game.

VILLAS PLAYERS / MANAGER

Ken McNAUGHT

Centre-half in Villa’s successful League Championship, European Cup and European Super Cup winning teams.

 

AMOO Ryan

Played for Aston Villa during the 2000’s, when first-team opportunities were limited.  An extremely gifted player.

 

BELFORD Dale

Goalkeeper who started his professional career with Aston Villa in July 1985. He moved on to Nott’s County in 1987.

 

BRADLEY Darren

England Youth international. Played for Villa 1983-1986. Moved to WBA and made over 400 league appearances.

 

BREMNER Des

Scotland international midfield player. Won the League Championship, European Cup, and European Super Cup.

 

BURKE Mark

England Youth international forward with Aston Villa from 1985-1988.  Also played for Middlesbrough & Wolves.

 

CAPALDI John

Midfield player who played for Aston Villa in the late 1970’s. Has extremely good passing skills.

 

CARRUTHERS Martin

Striker who played for Aston Villa from 1990 to 1993. Also played for Stoke City and scored over 100 league goals.

 

COMYN Andy

Centre back whose career began at Man Utd. Played for Villa 1989-1991 before his £200,000 transfer to Derby.

 

COWANS Gordon

England international. Won the League Cup, League Championship, European Cup, and European Super Cup.

 

COX Neil

Defender for England at U21 level.  League Cup winner for Villa in 1994. Also played for Middlesbrough & Bolton.

 

DALEY Tony

England international forward.  Played for Aston Villa from 1985 until transferred to Wolves in 1994.

 

DELANEY Mark

Wales international full-back. Played 193 first team games for Villa before retirement in 2007 through injuries.

 

 

DRAPER Mark

England U21 international midfield player. He was in the Aston Villa team that won the 1996 League Cup Final.

 

DUBLIN Dion

England international striker who played for Aston Villa from 1998-2004 and was in the 2000 FA Cup Final team.

 

DUDLEY Derek

Goalkeeper who started his career with Aston Villa in the 1980’s before moving to West Bromwich Albion.

 

EHIOGU Ugo

England international centre-back and League Cup winner with Villa in 1996. Moved to Middlesbrough for £8m.

EVANS Allan

Scotland international centre-back. Played in 1982 World Cup Finals. League, European Cup & Super Cup winner.

 

FARRELLY Gareth

Republic of Ireland midfield international. Aston Villa 1992-1997. Moved to Everton for £700,000.

 

FROGGATT Steve

England U21 international left-sided midfield player. Aston Villa 1990-1994. Also played for Coventry & Wolves.

 

GIBSON Colin

England U21 left back. League Championship, European Cup and European Super Cup winner.

 

HEARD Pat

Left-side player and member of Aston Villa’s European Cup and European Super Cup winning teams in 1982.

 

HENDRIE Lee

England international who spent 14 years at Aston Villa until 2007. Member of the 2000 FA Cup Final team.

 

JOHNSON Tommy

Midfield player or striker signed in 1995 for £1.45 million. Member of the 1996 League Cup winning team.

 

JONES Mark

Aston Villa 1979-1984. Member of the European Cup and European Super Cup winning squads in 1982/83.

KING Phil

Played in the FA Cup Final for Sheffield Wed. Scored Villa’s winner v Inter Milan in the 1994/95 UEFA Cup.

 

LINTON Ivor

Aston Villa player 1976-1982. Member of the European Cup and European Super Cup winning squads in 1982/83.

 

KINSELLA Mark

Signed for Villa in 2002 for £1 million. Won 48 Rep of Ireland caps and the Irish Footballer of the Year award.

 

McCANN Gavin

England international midfield player with Aston Villa from 2003-2007 before transferring to Bolton Wanderers.

 

MERSON Paul

Signed from Middlesbrough for £6.75 million. 21 England caps and 1988-89 PFA Young Player of the Year.

 

MORLEY Tony

England international in Villa’s League Championship, European Cup, and European Super Cup winning teams.

 

NORTON David

Defender or midfield player for Aston Villa from 1984-1988.  Equally at home playing fullback or in midfield.

 

ORMSBY Brendan

England Youth international. Member of Villa’s European Cup & European Super Cup winning teams in the 1980’s.

 

PEARSON Jon

Right-back who played for Aston Villa in the late 1980’s. Signed by Graham Taylor from Kidderminster Harriers FC.

 

PETTY Ben

Full-back or central defender with Aston Villa 1994-1999. Was transferred to Stoke City and then to Hull City.

 

PRICE Gavin

Gifted defender who played for Aston Villa during the 1980’s when first-team opportunities were limited.

 

REGIS Cyrille

England international. Played at Aston Villa 1991-1993 after great success with WBA and Coventry.

 

RICHARDSON Kevin

England international. Won the League Championship, League Cup and FA Cup with Villa, Everton & Arsenal.

 

RIOCH Neil

England Youth international. Aston Villa 1969-1975. Member of the 1971 & 1975 League Cup Final squads.

ROBINSON Phil

Aston Villa player 1985-1987. Played 500+ league games for Villa, Wolves, Birmingham, Stoke and others.

SAUNDERS Dean

Striker with 75 caps for Wales. Scored twice for Aston Villa in the League Cup victory over Manchester Utd in 1994.

 

SMALL Bryan

England Under21 international left back. Played for Aston Villa 1990-1996. Transferred to Bolton Wanderers.

 

SPINK Nigel

England international keeper. League, European Cup and European Super Cup winner with Aston Villa.

STAUNTON Steve

Played in 3 World Cup Finals with the Rep of Ireland and won 102 caps. Former Manager of the Republic of Ireland.

 

STIRLAND Gary

Skilful midfield player who played for Aston Villa in the early 1980’s.  A strong player with good passing skills.

 

SWAIN Kenny

Played for Aston Villa 1978-1983. Won the League Championship, European Cup and European Super Cup.

 

TAYLOR Ian

Aston Villa 1994-2003. Scored in the 1996 League Cup Final 3-0 victory over Leeds Utd. Also played in the 2000 FA Cup Final.

 

TEALE Shaun

Centre-back for Aston Villa from 1991-1995. A member of the League Cup winning team in 1994.

 

THOMPSON Garry

Villa striker from 1986-1988. Also played for Coventry & WBA. Made 487 league appearances, scoring 124 goals.

 

WALTERS Mark

England international who made his name at Aston Villa before transfers to Liverpool and Glasgow Rangers.

 

WARD Ian

Played for Aston Villa during the 1980’s, when first-team opportunities were limited.  A gifted utility player.

 

WILLIAMS Gary

Defender in the Villa team that won the League Championship, European Cup and European Super Cup.

ager for the day will be our Ambassador Mr Jody Craddock.