An Interview with Dr Brad Welling

I conducted a phone interview with Dr. Brad Welling of Ohio State University (OSU) on Wednesday, March 30th, 2011. I was introduced to the work of Dr. Welling by Marie Drew, chairperson of Advocure NF2. Based on his commitment to the NF2 community and his promising work with drug developments and naturals to find an effective treatment on tumors, I directed funds generated through 2010 fundraising, through AdvocureNF2, to his research efforts.

He asked my background. I told him about Camille, my daughter, 14 , who has NF2. She was diagnosed at 7 years old when she presented with tongue seizures that led to an MRI that led to emergency brain surgery to remove a tennis-ball sized tumor. Other signs, like her cataract, presented earlier but did not tip us off to her condition. Since her brain surgery, she has had MRIs every 6 months. She went to HEI to have surgery on one of her left vestibular schwannoma. The surgery was successful in removing the tumor and preserving her cochlear nerve but rendered her deaf in her left ear. Now she is legally blind in one eye, deaf in one ear but otherwise is a perfectly normal young lady. I told him that there are a lot of parents of NF2ers who are particularly motivated. I spoke about how NF2 is a condition that doesn’t manifest its ugliness right away. I can see where it can go and probably will go and we are in this unique position where we want to do everything in our power to help find a treatment, a therapy, now. Maybe it’s hopeful and wishful thinking but it appears that we are not that far away.


Dr. Welling: For my whole medical career, I have been telling my NF2 patients that “we are working on it but we don’t know when we’ll get to something”. But even though we are not there yet, at least in this past year, we have a couple of things that we are trying medically.

I don’t think we have the answer yet but we are further ahead now than when the NF2 gene was discovered in 1993. We are making inroads. I am encouraged about that. Its always a fine line you walk to try to show appropriate enthusiasm without getting people too overboard with ideas that may not quite have reached maturity yet.

R: We are always grasping for hope.

Dr. Welling: It is good to have hope, and it is also very nice to find people who are engaged such as you in getting to the answers. I appreciate, very much, your efforts and I hope that Camille will be the beneficiary of good things from your efforts. Obviously she will be by having devoted and concerned parents who are helping her through this.

R: Thank you.

Dr. Welling: A little bit about me. I have been at Ohio State University for 22 years. I have seven children. None of whom have NF2. I am on the CTF medical board. I was at their board meeting a couple of months ago. We sat down and discussed the barriers and obstacles that need to be knocked down. One of things that you alluded to is the unique nature of the disease. It really is unique. It calls for some out “of the box thinking” because I think we have a lot of researchers across the county working on cancer of various organs and tissues. With NF2 being classified as a “benign” disease, a rare disease, it doesn’t attract the kind of attention that we would hope for, for your daughter and other NF2 patients.

The pharmaceutical industry is less enthusiastic about helping on a drug cure for this than they are for something like breast cancer that is much more prevalent.

So far researchers to date have largely explored drugs that are already coming to market for other conditions that may interfere with known NF2 pathways.

We are part of that and have a couple of drugs that we are working on that are also being used for other types of cancers.

The difference is if someone has a malignant tumor that is going to kill them in a year, they can tolerate side effects that we wouldn’t even think about your daughter going through because her tumors are not going to kill her in a year.

We have to have drugs that are tailored to the disease that will be allowed to be taken over many years that will have a toxicity profile that are no worse than eating your broccoli.

It’s a unique disease and if I could do one thing in my career it would be to lend support to cure this disease because I have a lot of good friends who have this now, my patients over many years. I would love to help in some way. Its nice to have a chance to talk to you about this.

R: The NF2 community is excited to know where you are with your drug development and naturals testing.

Dr. Welling: We talked about some natural elements that we are collaborating with Dr. Douglas Kinghorn here at OSU. For many years in his career he has gone out to the forests of the world looking for botanicals that have influence in various disease processes.

He has a large bank of botanicals that he has been kind enough to collaborate with us on and we took about 20 of them and screened them for effectiveness against a variety of our cell lines including Schwannomas and Meningiomas. Some of these cell lines are from mice models and some are from human patients that have donated to them.

We have found 3 and maybe a 4th that are showing good activity. By activity, I mean that at a very low concentration that they kill ½ of the cells over a period of time. We are encouraged by this.

Dr. Kinghorn is helping us because his expertise is in purifying compounds and identifying botanicals that have efficacy against various types of tumors. I think he is a great collaborator.

As far as 2 of the drugs that were developed here at Ohio state, they are not naturally occurring elements but were derived from some things that we know about.

AR-12 (derivative of Celebrex)

We were quite enthusiastic about the results we were getting in our cell cultures, and it’s not quite as good as AR-42, another product we are working on with Arno-Therapeutics, which seems even more promising. It does slow the tumor growth.

AR-42 (HDAC inhibitor)

We have seen a fairly good reduction in Schwannoma growth in our xenograph models . We have not yet looked at genetic models. These are so the knockout mice that we have engineered in where we collaborationed with Dr Giovannini. We have several strains of knockout mice. The reason we use xenograph mice initially is because we know with certainty how much tumor we put in. We can more easily monitor them and we have quicker results. With the genetically engineered mice we knock out the nf2 gene and watch for schwannomas to grow. Sometimes it takes a year to get these tumors to grow. And then it takes a lot more time but it’s another good screen that we hope to get to with use for some of our most promising candidates. As far as the AR-12 and AR-42, they are in clinical trials for other disease processes right now which is fortunate in a way it because Arno-Therapeutics group is looking to help us looking in assessing for safety and the toxicity profile in these drugs.

The efficacy is not yet known. With AR-42, they are looking at studying it for cancers liquid tumors like leukemia and lung cancers, and the results are not yet out as far as how well they are doing. There are still in the middle of those trials. It does give us some valuable information.

We have to be a little bit careful with this, Phase 1 trials are to see how well the drug is tolerated in people. That’s important. However, NF2 patients have an underlying mutation and the way they handle a drug may be different than patients who do not have NF2.

We have to be cautious to say “hey all these volunteers took AR-12 for 6 months and did fine with no problems” and it might not be quite the same with folks who have an underlying mutation.

One of the roadblocks is that because it’s a rare disease and because we have 300 drugs we would like to try. We don’t have enough patients to do good clinical trials on 300 drugs. We probably need to identify 2 or 3 choices and then enlist the help of the NF2 community to do some good drug trials at that point.

We don’t have the luxury of having many participants for these studies to help us with this. To get 200-300 patients would be difficult. By the time you move on to Phase 2 you need lots of patients.

The more prevalent the disease, the easier to get patients to participate.

I have sensed tremendous support the NF2 community for any kind of drug trial and sometimes the difficulty is holding back the NF2 community. Everybody will jump on the bandwagon before we are sure we have the right drug. If there is no downside to it, I don’t really fight it regarding drugs over the counter.

A lot of people are trying many different things and I’d like to bring some sense to that. “Some over-the-counter compounds might make sense to use and this one others may not make any sense to use.” Hopefully, we can help with that part of it and eventually get to the most promising candidates.

It’s very frustrating for us as clinicians, as well as parents and patients that have NF2 that we don’t have that information yet. We are getting closer but it’s painfully slow.

In that particular point, I have advocated to our CTF colleagues, and DoD funding, as we start to do human trials, that we go ahead and include patients that have unilateral vestibular schwanomas VS’s and meningiomas because there are far more of them that can be involved in these trials. One of the drug trials we are working on (Lapatinib; PI Jaishri Blakely) is a drug that is being used in both our NF2 patients and our unilateral VS patients. What we are doing is just a Phase 0 trial. Clinicaltrials.gov, study #NCT00863122

The drug is given 10 days prior to surgery. After 10 days, we remove the tumor and assess to see if the drug is getting into the tumor and if we can see any activity of the drug against the tumor. This is a study that in a way is broadening the number of patients that can participate because we are inviting our patients that have Unilateral Schwannomas. Even though they don’t have the NF2 per-disposition gene mutation throughout the body, in the tumor itself they have both NF2 genes knocked out which is the same thing we are seeing in our NF2 patients, it is one way for us to expand the pool of participants in a drug trial. I think it’s a reasonable way to go.

The role of Arno-Therapeutics

Arno-Therapeutics is very valuable as a partner in this. We need folks who can lend financial and drug development support put some money in and we are happy they are helping us here at Ohio State. I think they are interested because we have shown some reasonable preliminary information in our cell cultures and in our mice, but also because there are other applications for these drugs in other pathway tumor types.

A lot of pathways that we know about in Schwannomas are shared in other tumors. Those are getting first priority as far as clinical trials. We are trying to get these things moved forward in our NF2 patients.

Naturals

Dr. Welling: One of the things that the NF2 community has done that I appreciate is that they’ve told me what they’re taking. There is a lot of interest in the Bio30™ and Artepellin C (ARC) and CAPE (Caffeic Acid Phenethyl Ester). All of these come from Propolis.

There are multiple different elements that make up Propolis which comes from bees wax. It is a substance that is used to protect the beehive. It has been known for eons to for many different uses (Egyptians, Incas). There are more than 180 different compounds.

Some of them have biological activity depending on where the bees are found around the world:

  • CAPE – one of the main compounds in Bio30™ from New Zealand
  • ARC – from Brazil
  • Chrysin – red Propolis from Brazil and China (does not have CAPE or ARC in it)

CAPE and ARC

Have been tested by Dr, Maruta and Dr. Shanta Messerli to see what kind of activity they have and they have shown some effectiveness against Schwannoma-like cells. The Xenograph model used in those studies take some cells that were transformed from patients with NF2 so that they grow well. But the cells are a little more aggressive than conventional Schwannoma type of cells.

Two Studies have been done. Dr. Maruta has been a proponent for looking at propolis and Dr. Shanta Messerli has done some nice work on these things. Both of the CAPE and the ARC have shown to inhibit Schwannoma like cells (HEI 193 transformed human Schwannomas) and have shown to help inhibit malignant peripheral nerve sheath tumors like the folks with NF1 get. We have not yet tested these. We have just got some pure compounds that we can use that are purified.

I think you have to be careful to know exactly what out of 180 compounds is actually active. Since people are taking this, it may be good to test the whole things against the tumors, but then the actual elements that are active are not known.

We are just getting our hands on this. There is a collaborator in Japan that has great interest in Propolis derivatives. It is certainly one of interest to us. We know that there are several different mechanisms proposed for the action of CAPE, one is an Antioxidant.

The antioxidant effect is that it seems to induce cell death. Another is vascular endothelial growth factor (VEGF) and there has certainly been a lot of interest with Dr. Plotkin’s and Dr. Blakely’s work with the VEGF inhibitor in Avastin also known as Bevacizumab. So if this Propolis has something in it that keeps the blood vessels from growing into the tumors (VEGF inhibitors) that would be a useful effect. If it can induce the tumors to die that would be a nice thing and it seems that it is also effective against pancreatic carcinomas and one or two other carcinomas.

It certainly is one of the things that I am interested to dig into a bit more. We would like to try it against some of our cell lines that are a little more pure and haven’t been transformed so much. The HEI (House Ear institute) cell lines are useful, but not exactly very representative of what the cells are that we see in tumors coming out of an NF2 patient.

Another thing CAPE has been shown to do is to sensitize tumors; particularly Glioblastomas to radiation and we are interested in that effect. Perhaps we can sensitize these tumors so that we could give a smaller dose of radiation and not damage the surrounding structures. We have not tested these in Schwannomas but it is interesting to see that CAPE has been shown to have a radio-sensitizing effect against Glioblastomas.

Other people have also reported lower blood pressure and cholesterol and its been proposed in the treatment of the hardening of the arteries. All of things are interesting and if you’re are going to have side effects, those are the kind of side affects you want.

CD is Cyclodextrin and it helps the Bioavailability of most naturals. It is vehicle by which we can improve the absorption of CAPE.

Curcumin

There are drugs that have come from botanicals like Bioperine, from black pepper, that also help the Bioavailability of other nutrients. Bioperine may help the efficacy of, for example, Curcumin.

Curcumin is not very Bioavailable if ingested but if taken with Bioperine it helps the Bioavaility of it.

In one study that we did not do, but other investigators did, the Bioperine increases the Bioavailability of Curcumin substantially and helps to inhibit the Cancer cell proliferation up to 86%.

Curcumin is from Tumeric, a commonly used spice. We have purified Curcumin to work with and its one that we would like to study in our cell cultures and our mice but we haven’t done anything with it yet.

The green tea extract – EGCG (Epigallocatechingallate) – That also seems to holds some promise. The Sulforaphanes that are found in broccoli …I like that idea …we could make our kids eat their broccoli.

One of the others is Resveratrol and does seem to have good activity in our cell cultures.

Honokial – Dr. Jonghn Dae Lee presented some information last spring at the CTF meeting on their work on Honokial. They did some testing with schwannomas cells and showed some substantial reduction. That is an encouraging compound. It comes from the magnolia tree and I am not sure about its commercial availability. We have not tested this. We don’t have a purified compound, Dr Kinghorn’s lab has been excellent for separating these compounds and purifying them.

Mice – Genetic Engineered vs. Xenographs

We talked a little bit about the mice. The Xenograph mice which are immune compromised. Some people don’t like that model because we are taking a mouse using mice that already have a compromised immune system. Both of these models (Genetic Engineered vs Xenographs) have their pros and their cons.

One of the things that is very useful is we can put in a controlled amount of tumor we can image them with MRI scans or fluorescent tags to see which of the active cells are still available by a screening device.

We can screen a large number of mice at a lower cost than when we genetically engineer them. Dr Giovanni has let us have some of his NF2 mice and we have engineered some of our own lines.

We have developed another knockout mouse. Housing them for a longer period of time than the Xenograft mice is expensive. In an ideal world we would test both types of mice with highly promising drugs. We have to test these in humans because mice are not humans and if we find drugs that are well tolerated or already being taken, like botanicals, it would make some sense to study them if we have reasonable hope from our pre-clinical work.

R: If you identify 3 or 4 that you think are working, could you have 50-100 people try each of these and then send MRI reports back to you?

Dr. Welling: That’s exactly what we have to do. We probably would need to do a placebo too. We would want to make sure to not attribute an effect to a drug that was actually just the natural history of the tumor.

Once we have the compounds solidly lined up in our minds by those most likely to be successful, especially things that are already available or already been taken, we look forward to clinical trials.

Avastin is $15,000 a month. Curcumin, you can buy at the health food store. It makes sense to me to try to find agents that are already available.

There is not any great interest in the pharmaceutical world to push these forward naturally occurring elements which are already available over the counter because they cannot make any money on them and would not be able to recover any investment in them. They are already low cost.

What you say is exactly the way we want to go. When we are confident we have good agents, we want to start some clinical trials.

R: This is something we can do. This appears doable.

Dr. Welling: Do we need to do safety studies with these drugs to make sure there are no adverse effects? I am not sure. People are already taking them without adverse effect. You almost need patients that haven’t already been on something to do this trial.

R: The biggest frustration is that no one has ever analyzed to see if there is tumor shrinkage with any of these naturals. There are no tangible results. If you could get real data through these trials.

Dr. Welling: In the Phase 1 trials to see if there is no side effects. Those are usually 20-30 patients.

In Phase 2 of the trials, we would look to see if there is some effect against the tumor. This is interesting. In most phase 2 trials we are talking about Cancer that is rapidly growing.

Most of the endpoints that are checked for is to see how much the tumor shrinks. In NF2, if we could just keep them from growing that would help a lot of people. If we could just show that stopped the growth that would be excellent for these patients.

R: That would be success.

Dr. Welling: It’s a different endpoint than we are used to. When we put these grants in at NIH, people who review them are people who are used to reviewing grants for malignant tumors. I hate to call NF2 tumors benign, I prefer to call them a cancer-predisposing syndrome because the effects of the tumors are every bit as devastating. Because its unique it takes a lot of finesse to get the national funding.

If its already a product that is already on the market, it may be more expeditious. Doing the studies of naturals is still expensive, but its not as expensive getting the drug through the FDA.

In order to know if these agents are actually working, the clinical trials must be well designed. People just sending their MRIs, if they are not standardized, can be a real bugaboo. Standardized MRIs are difficult to receive. It would need to be a very real, rigorous process, so that we get real good data to make a solid conclusion about whether a drug is working.

R: I think this is something that we could make happen. I know we would like to encourage you and support you in this endeavor.

Diet

Dr. Welling: Regarding diet, a healthy diet is a good idea. Whether it has any effect on NF2 is not sure but always a good idea. Not only do we think this is important, but also think exercise, intellectual stimulation and a healthy environment may make more of a difference than we think.

There are some interesting things that the brain puts out that suppress some tumor types. It would be remarkable to see if we could intervene in that kind of way.

R: Should we be eliminating sugars.

Dr. Welling: I don’t see any evidence at this point that says elimination is necessary, but moderation is important.

R: You’ve been very generous with your time. Thank you. I would like to continue the conversation in the future and if there is anything that I, Advocure, or the NF2 community can do to help your research, please be frank and let us know.

Dr. Welling: I appreciate that. Funding is very tight. I have not seen it any tighter in my research career because of the national economy and the budgets at the national level.

Try to influence congress to fund the CDMRP-NFRP, DoD and the NIH also.

Let our congressman know that productivity and quality of life of these young patients will be worth their investment and if they can just see that down the road and if they can give Camille a botanical right now and not have to worry about all the expense that would come along from other interventions in the future.

One other thing, thinking about what we can do to accelerate the process, I have wondered what AdvocureNF2, NF Inc, CTF, NF2 Crew, and other various groups to see if there can be collaboration between all who support NF research to both increase the availability of patients and also to collaborate with efforts to lobby our congressman. I think everybody has the same goal and that is to cure the disease and any collaboration can only help.

Funding

The most important thing that you can do is continue your efforts. It is so expensive to do this work. I don’t mean to discourage you but it takes about 12-15 million dollars to bring a drug to market for any type of application.

In addition to your seed money, which has been very helpful, your influence with congress, with the funding agencies and NIH to recognize that this as an important problem, a devastating problem, we need to let them know that we do appreciate the funding for all this scientific work.

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