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Recently by Raymond DuBois M.D., Ph.D

At MD Anderson, we continue to focus on improving the effectiveness of cancer treatments for our patients.

Today, with the announcement of the new Institute for Applied Cancer Science (IACS), we intend to develop a more robust process for testing new cancer targets and drugs. The institute will make that possible by accelerating the translation of scientific discoveries into new, safe and effective drugs for cancer patients.

In 2011, we reached the 40th anniversary of the landmark National Cancer Act, heralded in when President Richard Nixon declared a "war on cancer" in 1971 and increased the federal dollars devoted to winning that war.

While far too many people still die from cancer, real progress has been made. Between 1990 and 2007, death rates in the United States for all cancers combined decreased by 22% for men and 14% for women. This means that 898,000 fewer people died from cancer during this time period (American Cancer Society, Facts & Figures, 2011).

Leaky pipeline for new drugs

This progress we've achieved in curbing cancer death rates is a direct result of ongoing drug discovery and development, an incredibly time-consuming and expensive endeavor.

According to statistics from the American Association for Cancer Research, completing the clinical trials and getting Food and Drug Administration approval for every cancer drug that makes it into the clinic takes more than seven years and $1 billion.

Molemeasurement.jpgRecent results, just published last week in the Journal of the National Cancer Institute, indicate that treatment with the selective COX-2 inhibitor celecoxib resulted in a 62% reduction in non-melanoma skin cancers, the most common cancers.   

After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, non-melanoma skin cancer history and patient time on study, the number of non-melanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the number of basal cell carcinomas (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and squamous cell carcinomas (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032).

Importantly, there was no significant difference between the number and extent of cardiovascular side effects between the placebo and treated group. This is an interesting study and offers some hope for the development of a chemopreventive approach for non-melanoma skin cancer.  

The reduction in skin cancer incidence in this study was much greater than that seen with the use of sunscreen. One of the investigators (Pentland) had already shown that COX-2 appears to play a role in sunlight-induced skin cancers.

We have known for a couple of decades that non-steroidal, anti-inflammatory drugs (like aspirin and other NSAIDs) reduce the risk for colorectal cancer and possibly other cancers. Recent evidence supports the reduction in risk for colorectal cancer in long-term NSAID users as well.  

Celecoxib is a drug that is widely used for treatment of symptoms associated with arthritis and has been studied extensively in several pre-clinical cancer models. It is effective in reducing tumor burden.  

Results from this recent skin study are exciting and I wonder if it means that future sunscreen lotions could be developed that might contain COX-2 inhibitors?

Raymond DuBoisRecent findings published in the Journal of Clinical Oncology suggest that aspirin may play a role in reducing the recurrence of breast cancer in women who have been treated for that disease.

 

Dr. Michelle Holmes of Brigham and Women's Hospital in Boston and her colleagues studied self-reported data from 4,164 nurses who had an earlier diagnosis of breast cancer. They found that nurses who reported taking aspirin two to five days a week (often for problems unrelated to breast cancer) were 60% less likely to have a recurrence of breast cancer than their counterparts who did not take it, and 71% less likely to die from the disease.

 

Based on this study, scientists can't confirm a direct cause-effect relationship between lower breast cancer recurrence and aspirin use. However, it has stimulated a lot of discussion about the role of inflammation and anti-inflammatory drugs, like aspirin, on cancer.

 

Inflammation can open window

Inflammation is the body's response to an assault, such as an injury or infection. The body retorts by producing chemicals that signal immune cells to rise up, attack and kill the invading germs. Unfortunately, in the process they also can damage surrounding tissue, leading to pain and redness, and in some cases of chronic inflammation, open a window for uncontrolled cell growth -- which is cancer.

 

Certain drugs known as NSAIDs (non-steroidal anti-inflammatory drugs), including aspirin, ibuprofen and other over-the-counter and prescription medicines, have been known to reduce inflammation. Since the 1970s, we have known that these drugs work by inhibiting the production of prostaglandins, body chemicals that are necessary for blood clotting and that also sensitize nerve endings to pain.

 

NSAIDs can block two different cyclooxygenase (COX) enzymes, COX-1 and COX-2, which are produced by the body at sites of inflammation and also are produced by some precancerous tissues. COX-1 and COX-2 are key players in the conversion of certain fatty acids into prostaglandins, which in turn are associated with inflammation.

 

Aspirin and other aspirin-like drugs (called NSAIDs) can block both COX enzymes. However, they also can cause medical problems, such as stomach bleeding, when taken regularly for long periods of time. To try to circumvent these side effects while still providing relief against inflammation, in the early 1990s pharmaceutical companies began developing NSAIDs that inhibit only COX-2 enzymes (sometimes called COXIBs) and were marketed as Celebrex.

 

NSAID-cancer prevention connection

The connection between NSAID use and cancer prevention has been studied for a few decades. Scientists conducted a series of animal experiments to see if NSAIDs might inhibit the occurrence or growth of colorectal cancers. They found that, in fact, the colorectal tumors regressed in animals given NSAIDs. Later, randomized clinical human trials established that two NSAIDs (sulindac and celecoxib) suppressed adenomatous polyps and caused existing polyps to regress in patients with familial adenomatous polyposis (FAP, a rare hereditary condition).

 

The next step was to see how these medicines might affect people who didn't have FAP but might still be at risk for colon cancer. During the 1980s, epidemiologists began collecting evidence from population studies showing that people who reported regular NSAID use had a lower incidence of adenomatous polyps and lower colorectal cancer death rates. These results indicated a possible protective effect against colon cancer from NSAIDs for the general population.

 

In my laboratory in the early 1990s, we began investigating why NSAIDs might convey this protective effect. My research team and I discovered that some intestinal epithelial cells made significant amounts of the COX-2 enzyme in response to growth factors or tumor initiators. This led us down a path of discovery that connected the two and helped explain, in part, how selective COX-2 inhibitors can reduce the risk of some cancers in people.

 

Scientists moved forward to test this theory in human patients. Two randomized clinical trials conducted in the 1990s and early 2000s confirmed that aspirin suppresses the recurrence of adenomatous polyps in people with a previous colon polyp. What's more, other limited epidemiologic data has shown that NSAID use may be associated with a lower incidence of or death from cancers at other sites, including the esophagus, stomach, breast, lung, prostate, urinary bladder and ovary.

 

Unfortunately, patients at high risk for cardiovascular disease have more serious cardiovascular events when taking NSAIDs and selective COX-2 inhibitors at high dosages for prolonged periods of time. On the other hand, some patients can tolerate these medications without cardiovascular complications quite well, especially at lower dosages when given once daily.

 

Further NSAID study needed

Scientists and clinicians are now working to determine how NSAIDs might protect against various cancers, possible effects of the long-term use of these drugs, optimum dosages and contraindications. They also are studying the benefits and risks of NSAID treatment across a broad range of treatment regimens, outcomes and patient populations.

 

Evidence from the nurses' study suggesting that aspirin use may be associated with a reduction in the recurrence of breast cancer may provide one more piece to this complicated puzzle. It certainly will launch the field further into this line of investigation.

DuboisRN_post.jpgThe problem with the current debate about health care reform is that it's no longer a debate, but has instead disintegrated into a free-for-all. All sides have become so frenetic about protecting their own interests and hurling politically based accusations that reasonable and reasoned discourse has been lost in the melee.

We're treating health care reform as if it were "The Blob" from the old sci-fi B-movie, terrifying citizens as it destroys everything in its path. Health care reform isn't a monster and could be a godsend -- a crucial improvement to a medical system that's one of the best in the world, but one that has become too unwieldy and expensive. Improving our health care system will aid many people who aren't receiving the standard of medical care they deserve as American citizens.

So, let's step back, calm down and refocus. At M. D. Anderson, we see the sickest patients with the worst prognoses.

Ensure availability of best treatments
1) We'd like to be sure that all of our patients receive the best treatments available, if they choose to be treated. Our policy isn't to give up on our patients. We have witnessed many instances where patients were told they had no options, only to be treated at our medical center or to be enrolled in a clinical trial and respond to treatment. In a few cases, these patients were completely cured. In many cases, their lives were prolonged for years. And in innumerable cases, their lives were prolonged for several months to a year. The vast majority of families we work with say that they appreciate the extra time their loved ones were given, and their out-of-pocket costs were worth their extra days together.

As a result, the health care debate must revisit the issue of reasonable costs for a family with a seriously ill loved one. Guidelines need to be established for treating these patients appropriately, without crossing the line with unneeded tests or treatments that will have no impact on their outcome. Legislators should also factor in what's learned in academic medical center clinics -- that scientists and physicians track patient responses and return to their labs and clinics to improve their medications and refine their protocols. Our health care reform package must be flexible enough to allow for growth in knowledge and encourage strong support of biomedical research.

Establish a set of measures
2) A new health care plan must include a set of metrics that can measure the success or failure of its component parts. This means that the health care reformers must decide now what it is they're aiming to improve. If "reform" simply means "cost cutting," then the task will be fairly simple and the debate will center around "how much to cut." If the reform includes improving the clinical outcomes of patients cared for in the United States, then a completely different and much more intricate set of measures will need to be evaluated.

We must have a full understanding of the costs and benefits of different treatment options. We must also evaluate prevention measures and whether patients who smoke, overeat and avoid screening procedures should be penalized by the system, or whether patients who don't smoke and lead healthy lifestyles should be rewarded instead. In other words, reform might mean placing a "value" on different health care options or a relative "value" on different treatment options. On the other hand, through the very exercise of creating measures, we'll begin to see areas where we can truly cut costs and other areas where we must maintain a certain standard of care.

Make room for science, discovery
3) It's crucial that any measure of reform provide an opportunity for new science and discovery. There are many hospitals in this country that are focused more on research and academic endeavors. We must ensure that the health care reform agreed upon doesn't do away with the academic/research segment of our health care system.

Fifty years ago, childhood leukemia (ALL) was essentially a death sentence with only a 4% survival. Today, it's one of the most curable cancers in our armamentarium (75-80% survival) thanks to the devotion of generations of scientists and physicians who wouldn't give up. Funding this research wasn't cheap and it took a lot of faith before breakthroughs began to emerge. But today, what parent who has a child being treated for ALL wouldn't say those resources weren't well spent? What active, productive, happy adult who was cured of ALL would say the benefits to society weren't worth the costs?

In other words, we cannot lose sight of our goals in this stewing cauldron of arguments about American health care. We shouldn't become sidetracked or weary because the noise is so loud and the confusion so disheartening. We shouldn't be afraid of change. We shouldn't stymie progress just because we can't foresee the future.

By the same token, we will have to regain control of the issue. That means calming down, listening to all sides, making reasonable decisions, building in measurements for outcomes, and reconnoitering when the results are less than excellent. We will only succeed through acts of bravery, determination and compassion.

I believe that Americans are up to that task.

raydubois.jpgThe joint ASCO/AACR symposium held yesterday at the ASCO meeting in Orlando, co-chaired by myself and Rich Schilsky, was a tremendous success. Not only was it well attended, but the topics presented led to an active discussion with the audience.


It was led off by Michael Pollak from Jewish General Hospital in Montreal, who spoke about the link between sugar metabolism and cancer risk. Provocative data was presented showing links between IGF-1 and cancer. 

The second speaker, Dan von Hoff from TGEN in Phoenix, explained how the Hedgehog pathway works and three ways that it may serve as a target for the treatment of patients with basal cell carcinoma. Dan presented some early phase data from patients with advanced disease that had remarkable responses to drugs that target the Hedgehog pathway. 

Lastly, Garth Powis from M. D. Anderson described the most recent advances in the PI3K signaling pathway and new drugs being developed that target this signaling pathway. Although in early stages, this work seems very promising and likely will lead to the development of new targeted therapies for cancer patients.  
 
Thus, combining forces between ASCO and AACR worked well for this symposium. A similar "joint" symposium was held at the recent AACR meeting in Denver and it was quite successful.

I'm not sure what the future holds in store, but hopefully the new leaders of both organizations will be able to work together and continue to sponsor these joint symposia. Bringing together the laboratory and clinical scientists is quite informative and useful.
 


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