A Conversation with

O.M. Zack Howard, Ph.D.

Staff Scientist
Cancer and Inflammation Program
Laboratory of Molecular Immunoregulation
Center for Cancer Research

Q: What projects are you currently working on?

I work on tumor immunology. That is a fancy way of saying I’d like to find out how an individual’s immune system gets hijacked by a tumor. Currently, I’m pursuing projects related to CAM. We are looking at an inflammatory breast tumor model called 4T1. It’s a mouse tumor that is transplanted into another mouse and induces a cell type called a myeloid immunosuppressive cell – or MIC – that suppresses the immune system.

These MICs have a particular phenotype, and they cause T-cells – which should kill the tumors by any number of mechanisms – to stop proliferating and to become non-functional. The MICs do some other interesting things. They produce prostaglandins that cause a lot of physiological effects downstream ranging from pain to initiating a general inflammatory response. MICs are very potent inhibitors of the immune system in tumor bearing individuals.

The CAM modality that we’re studying at the moment involves Sheng Qi Formula (SQF), a Chinese herbal decoction that is commonly used in China to decrease the side effects of chemotherapy and as a stand-alone therapy. It’s a hot water extract of two plant roots. SQF has a potent inhibitory effect on MIC number and function.

Q: Is SQF a traditional Chinese medicine (TCM)?

It is based upon TCM. The original formula was an extract of milkweed vetch root and the other component is Chinese ginseng root. The SQF concoction is delivered orally to the animals and to Chinese patients. In China, it is used to decrease the side effects of chemotherapy such as cisplatin and drugs of that nature that are used to treat late-stage lung and other cancers.

In China, the SQF concoction is also believed to cause an enhancement of the chemotherapeutic effects in patients. We have not yet seen that effect in the mice, but we probably chose the wrong model for the initial testing. We have tested SQF in combination with taxol in this inflammatory breast cancer model. Because it is an inflammatory breast cancer, taxol is not the most efficacious therapy. We will repeat this study probably at the end of February 2008 with a different chemotherapeutic agent gemcitabine that will probably be more efficacious.

We’ve accomplished two things in the current study of SQF. First, we have a verification of the efficacy of this TCM agent in a mouse model. Second, we have identified the agent’s immune effect in this model, and that effect is to reduce the level of MICs. Following implantation of the 4T1 tumor, the MIC levels in a mouse can go up by 70%. The SQF formula can decrease MICs by at least one-half the elevated levels after implantation. SQF treatment reduced the tumor volume by 30% at 21 days following 4T1 implantation. So we have both an immunological and a therapeutic effect. We think we’re heading in the right direction.

Q: How did you become interested in CAM?

Over the years, I started looking at ethno-botanicals that had anti-inflammatory activity. We were looking to inhibit chemokine receptors. Back then, the pharmaceutical companies just ignored chemokine receptors. The companies were just interested in inflammation. They had COX-2 inhibitors, so they didn’t care about new ethno-botanicals. Actually, that’s not a bad approach in some cases, because it’s a regulatory circle. The COX-2 inhibitors suppress chemokine receptors, and if you suppress chemokine receptors, you don’t get cells migrating into other sites in the body as occurs with inflammation.

I searched for a source for natural products whose effects were specific to the chemokine receptors. It’s obvious that mankind over a period of thousands of years has evolved side-by-side with local environments. The ethno-botanicals found and used during the long histories of traditional medicines have given us things as obvious as aspirin and less obvious things such as Shikonin. Shikonin is the Asian version of aspirin. It has almost the same profile of efficacy as aspirin.

We looked at these natural products for a number of years. Eventually, “Big Pharma” got involved in research on finding chemokine antagonists, and they took the “rational drug development approach”. They have identified some things that are actually efficacious in animal models. A few of these agents have also made it to human testing. Basically, the question of whether chemokines are a good target has been addressed, and the answer is “yes”.

The answer is less clear about whether chemokine-antagonists can be used to prevent or treat cancer. However, the initial data suggest that some of the chemokines are intimately involved in the progression and survival of individual cancer cells. At that point, we decided that as tumor immunologists maybe we need to look and see if there is a way to use the same ethno-botanicals in TCM for regulating tumors.

Q: Do you see any specific future research opportunities in TCM or any other kinds of CAM interventions?

I’m really excited about our SQF research. I think this program still has another 5-10 years to run, because we don’t really understand the role of the MICs.

Regarding the field of CAM, we barely understand the mechanisms for many interventions. That’s not unusual for Western medicine either. For example, I recently attended a seminar on vaccine research. Vaccines in this country have been the focus of empirical and hypothesis-driven research since 1893. Despite that, the scientist leading the recent seminar admitted that we still don’t understand the basic mechanisms of how they work!

I think we’re going to learn a lot about the way the human body works by investigating the use of these CAM approaches. In addition, in recent years we went from being very isolated from these traditional Eastern medicines to now being exposed to TCM and being able to mix and match CAM with Western medicine. If we don’t understand what we’re doing – and we don’t – we will have innumerable, unfavorable effects. For example, I was at a meeting earlier this year where one of the presentations was about a dietary supplement that is available in a popular nutrition store and is reported to have a positive effect in women. The researchers gave it to male rats with prostate cancer in a controlled system and discovered the agent made the prostate cancer worse! That’s just one example of the necessity of fully understanding when and to whom a CAM therapy should be given; this knowledge will give us a better understanding of how CAM therapies interact with each other and in combination with Western medicines. I think it is going to take us 25-50 years of additional research to begin to figure it out. All of that research and experience is going to benefit humanity, because it’s going to allow us to better understand our bodies and ourselves.

For more information on Dr. Howard, please visit http://ccr.cancer.gov/staff/staff.asp?profileid=6249.