Source: www.onclive.com
Author: Jane de Lartigue, PhD

Brian L. Schmidt, DDS, MD, PhD, is a specialist in head and neck cancers whose research focus includes an exploration of the biological and molecular mechanisms of pain related to cancer and associated treatments.

He is the director of the New York University (NYU) Oral Cancer Center and of the Bluestone Center for Clinical Research, and a professor of oral and maxillofacial surgery at the NYU School of Dentistry. In June 2016, the National Institutes of Health awarded Schmidt and colleagues a $1.2 million grant to study gene therapy for the treatment of patients with oral cancer pain.

Schmidt talked to OncLive about the difficulties of studying cancer pain and developing new drugs.

OncLive: How has our understanding of the mechanisms of cancer pain changed in the past decade?
Schmidt: The field was developed probably in about 1999. That’s the first publication that I’m aware of that looked at mechanisms in terms of using preclinical models, and by that I mean animal models. Before that time we really had no understanding of basic mechanisms, so there’s been significant advancement over the last 10 years.

Could you briefly describe our current understanding of how cancer pain develops?
Let me tell you what it’s not, because I think that’s important. For many years, people were writing about it but we weren’t testing the possible mechanisms, and what people were writing turned out probably not to be true.

It was initially thought that the pain was due to the cancers growing and pressing on the nerves and we clearly don’t think that’s the underlying mechanism now. Possibly in some cancers that plays a role, but this whole idea of “pressing” really doesn’t work because it’s pretty hard to compress a nerve and there are actually a number of tumors that are not cancer that can compress nerves and those don’t hurt.

There might be a circumstance, for example, if you had a cancer in a perfect location, either let’s say in your leg where the femoral nerve is, or in the paravertebral skeleton where you have what are called spinal roots. In these cases, the cancer could press on the nerve and it would hurt, but that’s probably not a common mechanism.

Probably the best explanation for cancer pain we have is that the cancers produce a number of different molecules—and that depends on the type of cancer—that sensitize the nerves, which makes them respond to stimuli that’s normally not painful. And so the nerves that are surrounding the cancer become fragile, for lack of a better term, and those nerves fire in response to minimal stimuli.

What is the most effective therapy currently available?
I can tell you what’s most commonly used and its effectiveness is highly variable. We’re basically using the same drugs that have been used for thousands of years for pain, which are the opioids. So the narcotics—morphine, fentanyl, methadone, oxycodone, hydrocodone—that entire class of drugs. That’s what’s most commonly used.

Have researchers made any headway in developing drugs that target the underlying causes of cancer pain?
No, they haven’t. Probably the biggest development, and it’s not really targeted therapy, but the biggest development has been for cancers that go to the bone. Those include breast cancer, prostate cancer, multiple myeloma, lung cancer—those cancers go to the bone and cause a lot of bone pain.

We started using a class of drugs called bisphos phonates, which inhibit the cells that break down bone. They specifically inhibit a cell type called osteoclasts. Those drugs work for some patients who have bone metastasis. But we have not discovered true targeted therapies, and one of the challenges has been that the same obstacle that is present for oncologists treating the cancer has also proved an issue for pain physicians, which is that these cancers all behave differently, even within a specific type of cancer, so one colon cancer doesn’t behave like another one, for example.

So, where some cancer patients respond better to a particular drug than others, we think that the challenge of treating cancer pain is going to be the same—the drug will work for one patient but not for another. There is a class of drugs with an unusual mechanism of action—they are monoclonal antibodies that bind nerve growth factor. The history of those drugs has been interesting. Pfizer was the first company that produced one of these drugs and tested it in a clinical trial for low back pain, but the trial was stopped because patients on the drug were requiring hip replacement and it’s not entirely clear why. So there was a hold on the drug, but recently the FDA opened up the drug and so it’s going to be tested again.

It is thought that tanezumab would be very good for cancer pain, and Pfizer and Eli Lilly have joined together to test the drug. They’re both interested in seeing how it works for cancer pain.

What are the key unanswered questions relating to the effective treatment of cancer pain?
The key challenge, as I mentioned earlier, is going to be that all of the cancers behave differently, so they are independent of each other. It’s not like osteoarthritic pain, where the mechanism for causing osteoarthritic pain is, if not the same, then very similar between patients. Cancers are not that way. Even if you were to take a glimpse at the cancer at a fixed point in time, let’s say across 2 patients, now if you add the dimension of time, because cancers change over time, then in a patient 1 drug might be effective for a short time but then the cancer will change and it won’t be effective any longer. Again, this is similar to what oncologists face in treating cancer, where a drug is effective for a couple of months, but then patients stop responding and the tumor grows back.

Another challenge is that cancer pain clinical trials are also very difficult to recruit for because the patients are sick or dying, so they typically don’t want to enroll in studies. They are often on a lot of drugs. So of all the clinical trials, they are probably the most difficult for which to recruit.