AACR Conference 2008
ACKC attended the American Association for Cancer Reseaarch (AACR) Conference, which took place April 12-16, 2008 in San Diego. 29,000 researchers, advocates, and other interested members of the public attended. The following are summaries of some of the presentations.
AV-951 in Phase 1 Trial in the Netherlands
At the American Association for Cancer Research in April 2008, Ferry Eskens of the Erasmus Medical Center in Rotterdam presented in, an oral session, the results of a Phase 1, single-center trial of the anti-angiogenic drug AV-951 in 41 solid tumor cancer patients, 9 of whom were RCC patients (others included colon, lung, pancreas, and other tumor sites). AV-951 is a highly potent drug that has inhibitory activity against VEGF Receptors 1, 2, and 3. The objectives of the trial were to determine the maximum tolerated dose and dose limiting toxicities. Dosage levels were given of 1 mg, 1.5 mg, and 2 mg per day.
For the nine RCC patients, there were two partial responders, six with stable disease, and one with progressive disease. One responder, who was on 2 mg, was on treatment for 2½ years. The second responder, on the 1.5 mg dosage, was on treatment for 9 months. The six patients with stable disease remained so for periods ranging from 3½ months to 12 months. Their dosage was either 1 mg or 1.5 mg. The final patient progressed after two months. The response rate for all 41 patients was 33%.
The investigators started out with 8 patients on the 2 mg dosage but found it to be too toxic so dropped the dosage to 1 mg and 1.5 mg for the balance of the patients. As is common with other angiogenic inhibitors, hypertension was an issue, occurring as a grade 3 event in 62% of the patients. There were no grade 4 events and all side effects were controllable by medication. One patient reported grade 3 fatigue. Otherwise, all other events were limited to grades 1-2. Hoarseness was the most prevalent grade 1-2 at 56% of patients. Little is understood about the mechanism of hoarseness in connection with these types of drugs.
In terms of clinical laboratory abnormalities, there were a number of grade 3-4 liver enzyme abnormalties. And, for the 1.5 mg dose, 44% of the patients had grade1-2 proteinuria (protein leaking from the blood vessels into the kidneys).
The investigators concluded that AV-951 has a MTD (maximum tolerated dose) of 1.5 mg/day given for 28 consecutive days with the next 14 days off treatment with hypertension the most prevalent dose-related side effect, but one that could be controlled by medication.
AV-951 is a highly potent molecule. Dr. Eskens put up a slide in his presentation showing a chart of the IC50 values for various tyrosine kinase inhibitors (TKIs). AVI-951 is a TKI that inhibits VEGFR-1, for example. IC50 is the necessary concentration of AV-951 to inhibit the biologic functioning of VEGFR-1 by 50% in vitro, in this case .21 nanoMolars (nM). By comparison, axintinib, also an inhibitor of VEGFR-1, has an IC50 value of 1.2 nM. Sutent is not an inhibitor of VEGFR-1. The following chart compares the IC50 values for a few TKIs (ref. JCO, 2007, 25).
|IC50 Values in nM|
The potency is reflective in the MTD: Av-951 1.5 mg/day, axitinib 5 mg BID, Sutent 50 mg/day, and Nexavar 400 mg BID. Of course, being more potent doesn’t necessarily mean being more effective. Sutent and Nexavar act on other targets as well. But axitinib concentrates on VEGFR-1, 2, and 3 also so it will be interesting to compare the clinical results of the two drugs in RCC patients.
Aveo Pharmaceuticals, AV-951′s manufacturer, is preparing to test the drug in two trials dedicated to RCC patients.
Phase 1b AV-951 and Temsirolimus (Torisel)
This trial is testing the maximum tolerated dose and dose limiting toxicities of the combination of the two drugs, with ascending doses of AV-951 at .5 mg, 1 mg, and 1.5 mg/day for 21 days with discontinuation for 7 days and temsirolimus escalating from 15 mg – 25 mg every 7 days. To be eligible, the patient must have a clear cell component, one or zero prior VEGF inhibitor therapy, no prior mTOR inhibitor therapy. They expect 32 patients to accrue to the trial, which commenced in November 2007 and will run through April 2009. Current locations are UCLA, Moffitt Cancer Center, and Methodist Hospital in Houston with another site scheduled to open in Stanford University.
Phase 2 Multi-Arm Trial of AV-951
This Phase 2 trial will test response rate and will commence with a dosage of 1.5 mg/day for 3 weeks on and 1 week off, defined as 1 cycle. After 4 cycles, patients will be evaluated according to RECIST criteria for tumor growth and will be divided into the following arms:
a) patients with > 25% partial response will remain on the drug
- b) patients with < 25% partial response but also < 25% progressive disease will be randomly assigned to one of the following two groups:
i) continue on AV-951
ii) be placed on a placebo
for 3 cycles (12 weeks). After the 3 cycles, the groups are unblended. If the AV-951
has not had > 25%progression, they continue on the drug. The placebo group has
the option of going back on the drug.
- c) Patients with > 25% progressive disease are discontinued from the study
Eligibility for the study is one or zero prior treatments, no VEGF prior; all histologies are accepted. The accrual period commenced in October 2007 and the trial will run through March 2009. 200 patients are expected to be accrued in India, Russia, and the Ukraine.
Pankaj Bhargava, Aveo’s VP for Clinical Research, told ACKC that he hopes to have results for both the above trials ready to report at the ASCO 2009 Conference.
Identification of B7-H1 in the Blood of Kidney Cancer Patients
Xavier Frigola, Brant A. Inman, Haidong Dong and Eugene D. Kwon
At The AACR Annual Meeting in San Diego, Xavier Frigola and researchers from the College of Medicine at the Mayo Clinic in Rochester, Minnesota, posted the results of a study concerning the effect of the blood chemical B7-H1 in clear cell renal cell carcinoma (RCC) patients. The presence of the chemical is an ominous sign for cancer patients. Secreted by cancerous growths, expression of the chemical by as few as 5% of tumor cells can lead to a bleak prognosis down the line. A previous study at the Mayo Clinic by R. Houston Thompson (Cancer Research 66, 3381-3385, April 1, 2006) reported a five-year cancer-specific survival rate of 41.9% for patients with the presence of B7-H1 in their tumors versus 82.9% for those RCC patients without the presence of B7-H1. For the current study, Frigola et al.’s research found that B7-H1 acts as a profound suppressor of T-cells, weakening the immune systems of patients and making them vulnerable to a host of new diseases.
B7-H1 and the PD Pathway
B7-H1 is normal component of every healthy immune system and its function is to stop the immune response once the infection has been cleared. By inhibiting immune cells, the body protects itself from an overly aggressive autoimmune response. If one looks at an automobile as the immune system, then B7-H1 are the breaks of the car and other molecules are the gas pedal, but both are very important to control. Tumors in general and RCC in particular misuse this molecule in stopping every immune cell (T-cell) that goes to attack the cancer cells. The immune cells, ready to kill the tumor find themselves unable to “accelerate” because B7-H1 in the tumors pushes their break system and these cells die without doing their function (eliminate the tumor). Literally, the signal from B7-H1 causes T-cells to implode, and this mechanism is titled (fittingly) the Programmed Death Pathway (PD).
The Study and Results
Frigola et al. collected blood specimens from 58 RCC patients and 79 normal donors. The researchers found that in RCC patients, there is a distinct increase in blood serum concentration of B7-H1 when compared to healthy individuals. They also found that several different lines of cancer cells – kidney and bladder included – secreted B7-H1 when isolated in media. Specifically, the study found that B7-H1 leads to the apoptosis -signaled cellular death – of CD4 T-cells, and not CD8 T-cells. CD4 cells are also known as “helper T-cells,” and they are the critical group of T-cells that signal the presence infection along to other cells in the immune system, in order to elicit a full immune response. The elimination of CD4 T-cells represents a severe attack on the immune system; for perspective, CD4 T-cells are the immune cells whose destruction by HIV leads to AIDS.
Frigola proposes that the secretion of B7-H1 by tumor cells is likely a mechanism by which the cancer can inhibit anti-tumor immune response. He also recommends that any therapies planned against B7-H1 immune suppression must be sure to target no only cell-surface B7-H1 but serum molecules as well.
Smoking, Exercise, and Diet
On April 12, 2008, at the AACR Conference in San Diego, California, Memorial Sloan-Kettering Cancer Hospital’s Dr. Jimmie C. Holland hosted a series of speakers in a seminar on the topics of health behavior and lifestyle in cancer survivors. The United States is currently home to over 10 million cancer survivors whose health is generally worse off than that of the general population. For individuals who have survived cancer, the precautionary measures taken in lifestyle choices – exercise, diet and smoking cessation – are of even greater importance, and have frequently proven to be successful in the avoidance of further disease.
To many doctors, a cancer diagnosis represents a “teachable moment,” where patients can be motivated to enact positive lifestyle changes in order to improve their health in the face of the disease. However, according to a 2007 report comparing the health behavior of cancer survivors to the health behavior of non-cancer survivors, the lifestyles most cancer survivors go on to lead after their treatment are generally no healthier than those who have never had cancer. The point of Holland’s seminar was to offer ways to translate the health research science into usable health advice for cancer survivors.
The speakers Holland hosted – Jamie Ostroff, PhD, from Memorial Sloan-Kettering Cancer Hospital; Kerry Courneya, PhD, from the University of Alberta, Canada; and Wendy Demark-Wahnefried, PhD, from the MD Anderson Comprehensive Cancer Center – addressed the topics of smoking, exercise and diet among cancer survivors, respectively. Each offered compelling research supporting the positive effects of quitting smoking, exercising and eating healthily.
Smoking Cessation Following Cancer Treatment: Why Bother?
Dr. Jamie Ostroff, the Director of the Smoking Cessation Program at the Memorial Sloan-Kettering Cancer Center presented on the subject of smoking and the health of cancer survivors. Her talk covered all types of cancers, however, we know that smoking is the greatest known risk factor for developing kidney cancer. While it is known that if a smoker quits, after 10 years he or she has one-half the mortality rate from lung cancer than someone who continued to smoke during that period, there are no statistics available relating the benefit of quitting smoking for kidney cancer. According to Dr. Ostruff, the unfortunate fact is that smoking is nearly as prevalent among cancer survivors as it is among those without cancer. The known health risks from smoking aside, there are added dangers faced by cancer survivors. In addition to the threat of initial cancer recurrence, smoking also increases the potential for new cancers, and raises the risk of infection for those undergoing surgical cancer treatment by weakening the immune system.
Despite the obvious health risks continued smoking creates, Dr. Ostruff pointed out that the barriers to quitting faced by survivors are no less real. The psychological distress associated with cancer therapy makes smoking a coping strategy for many patients. The suddenness of entering cancer treatment can force patients with especially high nicotine dependencies to quit too abruptly to be successful. Another barrier is the high level of nicotine dependence and concomitant withdrawal issues. Patients often relapse soon after the completion of treatment and the apparent return of their health. Confirming this is the fact that, as studies have shown, the prevalence of smoking in adults (22%) is not statistically different for cancer survivors than for those without cancer. In the mind of the cancer patient, of course, there is the obvious question of whether or not there is even a point to quit smoking when the worst – cancer – has already happened.
Dr. Ostroff answered this question readily. The benefits of quitting smoking are quite significant and cessation can improve the prognosis of cancer survivors greatly. Statistics show that disease recurrence is lower, secondary cancers are fewer and overall quality of life is much higher.
The challenge for doctors, explained Dr. Ostruff, is directing patients to stop smoking while mitigating the barriers cancer patients face in quitting. She has been running her Smoking Cessation Program at Memorial Sloan-Kettering since 1999, and in 2007 worked with over 1,000 patients, who were referred to her by oncologists and surgeons at the hospital. For lung cancer patients, the program attained a rate of continuous abstainers of 70% one year after entry. However, for other types of cancer, the rate is lower.
In order to increase the cessation rates, Dr. Ostroff, a behavioral scientist, highlighted a strategy that involved anti-smoking intervention before patients even begin cancer therapy. The idea is to decondition smokers from the triggers that normally stimulate them to smoke, like their morning coffee, and instead place them on a cigarette schedule. This schedule is then tapered down as treatment approaches and eventually smokers are weaned completely.
Since most relapsers do so when they start feeling better, which is usually within a month after surgery, Dr. Ostroff speculated that earlier intervention would increase the smoking cessation rate, and she initiated a clinical trial in December, 2007, to test that hypothesis. For a detailed description of the trial, go to ClinicalTrials.gov at http://tinyurl.com/3lso75. Dr. Ostroff ended her talk by calling for more research in the biology of nicotine addiction and the use of biomarkers to “understand risk profiles and disease outcomes”.
We in the kidney cancer world have seen many clinical trials of targeted therapies documenting the recurrence rates, but none of these studies have included smoking as an independent factor. One way to do that may be to give the patient scheduled blood tests to pick up the presence of cotinine, which is a metabolite of nicotine and indicates the exposure to tobacco smoke. The trial results could then be stratified by smokers versus non-smokers.
The information Dr. Ostroff reported is of use to any cancer patient, kidney or otherwise, as it convincingly showed the benefits of quitting smoking even after a cancer diagnosis and suggested an effective method by which to do so. For further information on smoking cessation including available clinical trials and other resources to help one quit smoking go to http://www.smokefree.gov/.
Exercise in Cancer Survivors: Possible Mechanisms for Improved Outcomes
Dr. Kerry S. Courneya, Research Chair in Physical Activity and Cancer at the University of Alberta, Canada, delivered a presentation on the benefits of exercise in cancer survivors and offered some mechanisms for what the biological benefits of physical activity may be. Obesity and sedentary lifestyles are major risk factors for renal cell cancer but, like quitting smoking, many cancer survivors are no more likely to exercise or lose weight than non-cancer patients. For some people, the thought of exercise, like the thought of quitting smoking, is met with apathy, either because, as older survivors, they may not have time to really benefit from it, or, for those people who did exercise, it did not prevent them from getting sick in the first place.
However, Dr. Courneya pointed to several studies that showed a general improvement in the conditions of cancer patients who exercised regularly. In a landmark study of breast cancer survivors (Holmes, JAMA 2005; 293:2479-86), it was shown that the relative risk of dying from breast cancer was halved for survivors who walked an average of 3-5 hours a week at a normal pace (2-3 mph) versus their sedentary counterparts. The risk reduction was especially apparent in women with hormone-receptive tumors. The protective benefit of exercise was similar among overweight women (BMI ≥ 25).
Dr. Courneya also presented the data from his 2003 trial for breast cancer survivors that assayed the levels of biomarkers – blood chemicals and hormones known to be associated with cancer – in response to regular exercise. The study showed a distinct decrease in IGF-1, a signaling hormone that assists in cell proliferation that has been strongly linked to several types of cancer. The study also showed stimulation of Natural Killer cells, important agents of the immune system in combating tumors.
In summation, Dr. Courneya called for more epidemiological research studying the relation between physical activity and disease outcome in all types of cancers (in correspondence to ACKC he said that he will likely do a survey of kidney cancer patients at some point in the future). But he also called for randomized controlled trials to prospectively study the relationship between exercise and disease endpoints. To that end, they are initiating a three-year, multi-center trial in Canada for 1,000 stage 2 and 3 colon cancer survivors, after treatment, comparing exercise to standard care. This will be the first randomized trial that will study exercise and cancer disease recurrence as an endpoint.
Dr. Courneya made a strong case for the benefits of exercise in cancer survivors, in terms of both fitness and physiological well-being. But something perhaps even more compelling was brought up by a commenter following the presentation. The gentleman who spoke suggested that perhaps one of the greatest benefits to be gained from exercise is the resulting increase in self-confidence. As an oncologist himself, he explained that the fact that a patient’s doctor expects and believes them to be healthy enough to exercise while undergoing cancer treatment has an enormous psychological impact on the patient. It is not only humanizing in the face of punishing medical treatments, but it also indicates that the doctor expects the patient to live.
For more information on exercise and a healthy lifestyle, go to the website of the Centers for Disease Control and Prevention: http://tinyurl.com/46es3y.
Promoting a Healthy Diet in Cancer Survivors
The last speaker of the afternoon was Dr. Wendy Demark-Wahnefried from the MD Anderson’s Comprehensive Cancer Center speaking on the subject of diet in regards to post-cancer health. A healthy diet, like exercise and quitting smoking, is an important goal for any cancer survivor that is unfortunately not often enough achieved. Dr. Demark-Wahnefried’s discussion examined the various ways in which a person’s diet can affect their health and, like Dr. Courneya before her, the physiological mechanisms by which diet produces its effect.
In terms of benefits, there is growing evidence that, in addition to ameliorating co-morbidities such as cardiovascular disease, a healthy diet has an impact on cancer progression and recurrence. The American Cancer Society and the American Institute for Cancer Research (AICR) both emphasize the desirability of consuming more fruits, vegetables, and whole grains and limiting red meat consumption. AICR’s diet also restricts sugar and fats. Both organizations advise against using supplements to protect against cancer
Dr. Demark-Wahnefried highlighted the Women’s Intervention Nutrition Study (WINS) from 2006 as a telling example of the positive effect of diet, pointing to the observed 24% decrease in recurrence rates in breast cancer survivors who adhered to a diet in which no more than 15% of daily caloric intake came from fat versus a control group who ate a normal, healthy diet. Many women experienced weight loss while on this diet, and it is speculated that it wasn’t the low fat diet itself that led to the favorable prognosis but the concomitant reduction in Body Mass Index (BMI) that did the trick. (In kidney cancer, the data show that obese women (BMI ≥ 40) have nearly a five times greater risk of dying of kidney cancer than do women with normal BMIs.)
Dr. Demark-Wahnefried then went on to describe some potential mechanisms that might be causing these health improvements. Biochemically, adipose tissue (fat) is responsible for many cancer-causing activities within the body. Fat cells produce insulin, which in turn signals growth factors in the body and can fuel tumor growth; fat cells secrete oxidative chemicals, which can damage DNA and create cancerous cells; fat cells decrease levels of helper T-cells, important immune system agents in fighting tumor cells. By losing weight, one decreases their level of adipose tissue and hence decreases the frequency of any number of these negative, cancer-causing events.
Dr. Demark-Wahnefried cited the Nurses Health Study (Kroenke, JCO 23:9295,2005) in which the Western Diet – high in meat and refined carbohydrates – is not, in and of itself, known to be carcinogenic (though it poses a number of other health risks) was compared to the Prudent diet, high in fruits and vegetables, given to 2600 breast cancer survivors with a 9-year follow-up. The results showed no difference in cancer-specific mortality between the two groups, but a significant increase in other mortality rate, e.g. heart disease, among the Western diet group. She also cited a 1956 study on energy restriction – strict, straightforward caloric reduction of an otherwise standard Western Diet – on institutionalized, elderly patients, that showed the mortality rate and infirmary visits cut in half when caloric intake was decreased by 25%. Dr. Demark-Wahnefried suggested that just by cutting calories in general, a patient reduces the amount of fuel offered to adipose cells and in turn reduces the amount of fuel for tumor cells. Therefore, cutting down on fat itself may be a healthy move, but evidence that cutting food intake in general is perhaps more important for cancer prevention, at least for breast cancer patients. Unfortunately, Dr. Demark-Wahnefried did not cite studies in other cancer types such as colon, which clearly show a relationship between diet and risk. A Dana-Farber Cancer Center observational study in 2007 reported that colon cancer recurrences and mortality were 3½ times more prevalent among those who followed the Western diet than among patients who adhered more closely to the Prudent diet. Similar studies pointed to higher risks for colon cancer among adults who ate the most red meat. Dr. Demark-Wahnefried’s presentation was breast cancer-centric, which reduces its value for those of us concerned about other cancer types.
With respect to supplements, she pointed out that studies have shown that taking β-carotene increases the risk of lung cancer, head and neck cancer survivors receiving Vitamin E supplements were more likely to suffer a recurrence of cancer than a control group, and taking more than seven multivitamins per week increases the risk of advanced and fatal prostate cancer. The AICR recommends using supplements sparingly such as vitamin D for people who rarely go outdoors.
Depending on the population that is surveyed, 59-71% of cancer survivors are overweight or obese. Like smoking cessation, Dr. Demark-Wahnefried made clear that the most critical time to initiate a lower calorie, lower fat, healthier diet is immediately following the cancer diagnosis. By following strict dietary guidelines, a cancer patient’s risk of disease recurrence is reduced and his or her quality of life during treatment can be significantly increased.