Paul Cairns Project

On March 2, 2006, Action to Cure Kidney Cancer (ACKC) awarded a $45,000 grant to Paul Cairns, Ph.D., of Fox Chase Cancer Center in Philadelphia to purchase an important piece of equipment to help his laboratory develop a urine test that will detect all types of kidney cancer (renal cell carcinoma) in the earliest stages of disease. The new equipment will speed up the project and result in a more accurate test–which would be the first to be used against this silent killer.

Dr. Cairns’ work is part of the Early Detection Research Network, a program set up by the National Cancer Institute that issues grants designed to accelerate collaboration and speed up the translation of early detection projects to clinical settings.

For kidney cancer, early detection is especially critical. When the disease is confined to the kidney, surgery–either partial or complete removal of one kidney–enables many patients to live healthy lives for years. Because there is currently no effective method to screen for kidney cancer, and because the disease often presents no symptoms, more than 30% of patients are diagnosed after they have advanced disease. In its later stages, kidney cancer metastasizes– or spreads–to other organs, such as the liver, lungs, bone, or brain. Late stage patients have extremely limited treatment options and fewer than 10% survive five years.

This new piece of equipment–known as a real-time PCR (polymerase chain reaction) detection system and manufactured by Applied Biosystems–allows Dr. Cairns’ lab to further develop their urine screen for kidney cancer. The methodology is called quantitative real-time methylation-specific PCR, and it detects changes in patterns of gene methylation, one of the processes that can “hit” a tumor suppressor gene –turning it “off.” Gene changes are the trigger that causes a normal cell to turn into cancer. In the case of the urine screen, the trial panel of six genes that they are currently working with can detect kidney cancer in almost 90% of patients, with no false positives. Dr. Cairns’ lab is now looking to detect gene changes in individuals with early stage kidney tumors, specifically ones that are less than 3 centimeters in diameter.

How it works

To develop the screen, Dr. Cairns’ lab compared tumor with normal cells to identify target genes that were methylated in kidney cancer. Now, the task is to increase the number of genes in the panel in order to increase the sensitivity of the test, aiming toward 100% predictive value.

“For the urine screen–we use it (the new equipment) to analyze the methylation status of genes from kidney tumor cells, and then we use it to see if we can detect the same methylation in urine DNA of the same patients,” says Dr. Cairns.

It sounds much simpler than it actually is. The job is a massive puzzle that requires meticulous work to be performed repeatedly. The gene changes must be absent from the urine of healthy volunteers. The panel of genes must be representative of the changes that occur in all types of kidney cancer, from clear cell (which represents about 80% of kidney cancer cases) to papillary, chromophobe, and other rarer types.

“Kidney tumors, like all other cancers, are extremely heterogeneous in their genetics and biology,” says Dr. Cairns. “That’s why people with similar size, grade, and stage of tumors can have diseases that behave completely differently.”

By the time the project is complete, hundreds of urine samples will have been screened, each many times. The ABI system will both speed up the work and increase the accuracy of the test. Because the equipment works in real time, the lab can work more quickly: “We can read it off the screen in real time–we don’t have to do a gel analysis afterwards.”

The power of the machine also allows the test to be more accurate in two ways: sensitivity and specificity. The sensitivity is nearly ten times that of the technology previously used by Dr. Cairns’ lab–able to detect one cancer cell among 10,000 cells. Therefore the resulting test will have fewer false negatives–fewer patients will think they are disease free when they are not. A test with more specificity is less likely to produce false positives, or patients who think they have cancer but are then shown to be free from disease.

“I would say that kidney cancer is an understudied disease.” Dr. Cairns says that it is notable how little we know about kidney cancer compared to some other cancers. “One of the main areas I’m interested in is that we have absolutely no idea which are the key genes that drive kidney cancer. We know VHL [von Hippel Lindau], which is the predisposition gene, and we know it is almost certainly the first and key gene that is hit in the majority–but not all–cases of sporadic [non-hereditary] clear cell cancer. But when you model cancer by age and incidence, you can predict that there may need to be six or seven genes mutated in kidney cancer–and we have no idea what five or six of those are.”

The future

The ABI system purchased by ACKC provides quantitative data, which could open a window for Dr. Cairns into learning more about the behavior and natural history of kidney cancer.

“A quantitative assay really allows you to think about extending the use of methylation not just to early detection, but to prediction, prognosis, and monitoring,” he says. “Instead of just telling you whether a gene is methylated or not, it tells you the quantitative level of methylation.” Comparing methylation levels may help doctors confirm whether surgery has cured a patient or help detect recurrence early.

Dr. Cairns is interested in studying the gene profiles of “matched” pairs of tumors from patients with different outcomes to see if methylation can be used to predict whether a patient’s cancer will be indolent or more active. Once identified, new genes could be added to the screening panel.

Methylation might have other applications for kidney cancer patients. “Perhaps most interestingly, you might be able to use this to truly monitor a patient that’s receiving therapy,” Dr. Cairns says. “If the level of methylation dropped during chemotherapy, you could argue you’ve got a Œsurrogate marker’ of response.” Similar technologies are in advanced testing for some other cancers.

“Personalized or individualized treatment is a very hot area at the moment,” says Dr. Cairns. “I very much would like to work with tumors from patients who respond better and those who don’t respond so well to promising drugs for kidney cancer. Seeing which genes are methylated will help me learn more about the biology of how the tumors respond to these drugs.” Dr. Cairns says these genes could also be used to predict whether a patient might benefit from a particular treatment.

Dr. Cairns’ urine screen is still in feasibility testing. The next stage is to perform larger validation studies to prove the screen is effective and clinically valuable, and then it would move on to clinical trials to demonstrate its use in larger populations.

Challenges

While Dr. Cairns finds this an exciting time in cancer research, he can also see that patients might be frustrated with the slow progress of the field.

“Maybe one point that doesn’t get across to patients is just how stunningly complex cancer is as a disease, compared to other diseases,” he says. There are 140 different cancers, and each patient’s cancer can behave differently. Advances in screening, diagnosis, monitoring, and drug development have resulted in only a 10% increase in 5-year survivorship in the past 20 years. As we lead longer lives, one out of two American men and one in three women will face a cancer diagnosis at some point in their lifetimes.

“It’s a disease of life itself and to some extent a disease of aging. There are so many different genes and pathways that can go wrong. It’s quite incredible learning about the biology of the disease.”

Jay Bitkower, president of ACKC, sees the gift to Dr. Cairns as an exciting chance to make a difference in critical research that will benefit him, as a cancer survivor, and the many others affected each year. “Our members’ funding of the PCR system is an opportunity to help expedite Paul Cairns’ work to develop a urine screening test for kidney cancer, a therapeutic monitoring capability, and hopefully adding to the scant knowledge of kidney cancer genetics,” he says.

ACKC Presents $45,000 check to Paul Cairns.
From left: Patricia Todd, Fred Atkin, Paul Cairns, Ken Youner, and Jay Bitkower.

Download the Fox Chase Press Release (PDF) at the bottom of this page

Paul Cairns Project Summary

Kidney cancer kills, largely because it exhibits no obvious, consistent symptoms and because no diagnostic test is available for detection in the early stages when it is confined to the kidney and can be treated successfully. Because it is a relatively rare form of cancer, it receives short shrift from the government and pharmaceutical companies, the two largest providers of research funding in the U.S.

Yet when kidney cancer is detected early, it can be treated surgically to allow 90% of patients to live healthy, cancer-free lives for five years or more. If kidney cancer migrates to nearby tissue such as a lymph node, the survival rate drops to 60%. If it metastasizes to a distant organ, there is only a 9% chance of surviving five years. If kidney cancer could be detected in a routine lab test, many of the nearly 13,000 American patients it kills each year would stand a good chance of survival.

Paul Cairns, Ph.D., of the Fox Chase Cancer Center in Philadelphia is a pioneering researcher on the trail of genetic markers that identify kidney cancer. He has identified a panel of six genes in all of the different types of kidney cancer tumors that he has studied. In 2003, using his methylation [1] patterning hypothesis in a urine test, he demonstrated an 88% predictive value for kidney cancer – see article inre his early work http://www.hon.ch/News/HSN/516513.html. Based on these preliminary results, the National Cancer Institute’s (NCI) Early Detection Research Network awarded Dr. Cairns a $1.2 million 5-year grant to develop an accurate and reliable urine screening test for kidney cancer – see http://www.nci.nih.gov/newscenter/pressreleases/EDRN-BDL.

Dr. Cairns is seeking to acquire a real-time PCR [2] System, which will enable him to greatly increase the efficiency of his research and lead to an increase in the sensitivity of his test. Using this state-of-the-art technology enables researchers to identify one cancer cell in 10,000 normal cells, a tenfold increase in accuracy over the technology that Dr. Cairns used in 2003. His NCI grant does not cover the cost of such a system.

The PCR System will also support Dr. Cairns’ other work: developing a quantitative genetic serum test to determine the effectiveness of targeted drug therapies, e.g. Sutent and Sorafenib, in reducing cancer cell population for metastatic cancer patients; researching the genetic differences between indolent and aggressive tumors; uncovering new genetic markers for papillary type kidney cancer, etc.

Action to Cure Kidney Cancer is a grassroots organization of kidney cancer patients and their families that works to raise awareness of kidney cancer. ACKC works with government officials, individuals, and organizations to increase the level of public and private funding for kidney cancer research.

ACKC is greatly encouraged by Dr. Cairns’ work and supports his efforts to obtain a real-time PCR system for refining and expediting his research in the development of a urine screening test for kidney cancer. Therefore, we have undertaken to raise the funds Dr. Cairns needs for its purchase. The ACKC Board has voted unanimously to allocate $15,000 (half its assets) as seed money in a project to raise the PCR system’s total cost of $45,000.

ACKC is requesting contributions to fund the PCR System, which will support Paul Cairns’ work. Donations should be made payable to ACKC targeted for the CAIRNS FUND. Please go to our Donation section at http://www.ackc.org/donate to make your contribution.

For further information, see our extensive interview with Dr. Cairns and an article about his early research.


[1] Methylation is a chemical change in DNA that has the effect of turning genes on or off (in this case, turning off tumor suppressor genes).

[2] Polymerase Chain Reaction, a technology for amplifying and making copies of DNA in real-time. The PCR System is manufactured by Applied Biosystems Inc.