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Targeting Lymphoma's Command Center

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NEW YORK (Ivanhoe Newswire) - Non-Hodgkin's lymphoma is the seventh most common cancer in the U.S. Some forms of the disease respond well to treatment, but others are stubborn and aggressive. Now, a new discovery may change the way doctors treat the most difficult cases.

Gamers know to kill the enemy you must target the command center. Now, researchers are using that same concept to kill cancer.

"Cancer cells are machines. As we learn how they work, we can then learn how to block their functions," Ari Melnick, MD, Gebroe Family Professor of Hematology/Oncology, Professor of Medicine, and Director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College, told Ivanhoe.

Patients with aggressive forms of non-Hodgkin's lymphoma have too much of a protein called MALT1. It tells cancer cells to grow and survive.

"It basically is the crutch they use to walk on," Dr. Melnick said.

However, doctors have discovered that a new compound, known as MI-2, inactivates MALT1 and kills it.

"It's like hitting a command and control center, basically," Dr. Melnick explained.

MI-2 was tested in animals and human samples of lymphoma. The agent did not pose any toxicity, suggesting it could be a gentler alternative to standard chemo.

Jane Sarnoff just finished the standard treatment for her non-Hodgkin's lymphoma. It included four chemo drugs combined with other agents.

She says alternatives to chemo are greatly needed.

"It time for something like that," Jane told Ivanhoe.

Today, Jane is in remission. She hopes this new discovery will help others in the future.

The doctor saID the next step is to put MI-2 into pill form and test it on people with aggressive forms of non-Hodgkin's lymphoma. If successful in those trials, the drug therapy could possibly help other forms of lymphoma and with a variety of inflammatory and autoimmune disorders.

RESEARCH SUMMARY

BACKGROUND:  Lymphoma is the most common blood cancer. The two main forms are Hodgkin lymphoma and non-Hodgkin lymphoma. Lymphoma occurs when white blood cells, lymphocytes, grow abnormally. The body has two main type of lymphocytes that can develop into lymphomas, B-lymphocytes (B-cells) and T-lymphocytes (T-cells). The cancerous lymphocytes can travel to any different parts of the body, including the lymph nodes, bone marrow, spleen, blood, other organs, and can form tumors. Non-Hodgkin lymphoma (NHL) is the most common lymphoma cancer. Incidence rates for NHL have almost doubled since the 1970s. Of the 500,000 Americans who have lymphoma, around 332,000 have NHL. NHL is not a single disease. It is a group of several closely related cancers. The World Health Organization estimates 61 different types of NHL.  (Source: www.lymphoma.org)

SYMPTOMS: Common symptoms of NHL include swelling of the lymph nodes, fever, night sweats, lack of energy, and unexplained weight loss. The causes of NHL are unknown, but risks include: a family history, affected with an autoimmune disease, have received an organ transplant, have been infected with viruses like AIDS or Hepatitis C, or have been exposed to chemicals like pesticides. (Source: www.lymphoma.org)
 
STAGES:  NHL is divided into four stages:
Stage I (early disease): The cancer is only in one lymph node, in one organ, or in an area outside the lymph node.
Stage II (locally advanced disease): The cancer is found in two or more lymph node regions on one side of the diaphragm.
Stage III (advanced disease): The cancer involves lymph nodes above and below the diaphragm.
Stage IV (widespread disease): The cancer is found in several parts of one or more organs or tissues (in addition to the lymph nodes), in the liver, blood, or bone marrow. (Source:www.lymphoma.org)

NEW TECHNOLOGY: Treatment options can include:  watchful waiting, radiation therapy, novel targeted agents, stem cell transplantation, or chemotherapy. However, there is a certain subtype of Non-Hodgkin's lymphoma that is resistant to chemotherapy, called activated B-cell-DLBCL (diffuse large B-cell lymphoma). An international effort discovered the experimental molecule agent, MI-2, that inactivates the key protein that is responsible for the growth and survival of activated B-cell-DLBCL, known as MALT1. Researchers saID that a single drug cannot cure lymphoma, which is why they need to combine agents that can kill the different cellular pathways that lymphoma cells use to survive. They believe that the use of chemotherapy is too toxic and needs to be eliminated in treating lymphoma and the discovery of MI-2 will bring them closer to creating a combination of molecular targeted therapy regimens. MALT1 is the only paracaspase that is produced in humans and it is a particular protein that can rip apart other proteins. So, when MALT1 cuts proteins in activated B-cell-DLBCLs, it can activate growth and can stop other proteins from inhibiting that growth. When the researchers tested MI-2 in mice, they found that it had stopped the growth of cancer and did it without toxicity in normal tissues. Researchers believe that if MI-2 is successful in human clinical trials, then it could play a role in other diseases, including MALT1 lymphoma (a lower-grade type of lymphoma). It could also be beneficial for a variety of inflammatory and autoimmune diseases. (Source: http://weill.cornell.edu/news/releases/wcmc/wcmc_2012/12_10_12-2.shtml)

INTERVIEW

Dr. Ari Melnick, Professor of Medicine and Director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College, talks about a new treatment option for non-Hodgkin's lymphoma.

How frequent is non-Hodgkin's lymphoma diagnosed?

Dr. Melnick: It is the seventh most frequently diagnosed cancer. There are many sub types of non-Hodgkin's lymphomas and the most common are the diffused large B12 lymphomas. They make up about half the cases.

Are those the cases that are hard to treat?

Dr. Melnick: They're extremely aggressive; there are subsets of patients who are more treatable than others. In some of the patients, it's hard to distinguish which ones will be likely to respond versus those that don't. One of the features that were involved with this patient is identifying those features that predict which patients will respond well and then using experimental therapies to try to overcome their relative resistance to treatment.

What's the traditional course of treatment for lymphoma?

Dr. Melnick: Lymphoma has many different types, but for the common sub-types of lymphomas, especially those diffused with large B-cell lymphoma, the standard treatment is a combination of antibody therapy with four different chemotherapy drugs. That's what patients get.

Are there some that won't respond to that?

Dr. Melnick: There are some who won't respond to the current treatment, called RCHOP. So, most patients who are diagnosed with the disease will get RCHOP and then they're monitored closely to see how they do. If they're not responding, then more aggressive treatments are added to their basic treatment.

Some of those patients who don't respond have what you call MALT1, is that right?

Dr. Melnick: One way to distinguish a sub set of patients who have a more aggressive disease is based on a certain gene signature, which includes hyperactivity of a protein that's called MALT1. MALT1 is very important in these cells because it provides constant stabling to favor the survival and dividing of these cells.

So it kind of feeds those cells?

Dr. Melnick: It kind of tells them to grow and to not die. It keeps them going and basically is the crutch they use to walk on.

So you need to target that?

Dr. Melnick: Yes. One of the nice things about MALT1 is that it lies in between two of the major cancer pathways that drive this kind of lymphoma. So, there are often mutations that occur that cause this cancer growth pathways to be very active. They signal to MALT1 and then MALT1 transmits that information further inside the cell.

You have figured out a way to stop the communication?

Dr. Melnick: Exactly. It's like hitting a command at the control center so that the communication between the enemy and the actual factories that produce the cancer cells.

How do you do that?

Dr. Melnick: For the case of MALT1, working with colleagues who are experts in biochemistry, we developed a form of MALT1 that could be isolated and tested in a tube for its activity. It is difficult because MALT1 is not really active normally.  It's only active within cells, but not outside of cells. We managed to finagle and create a version of MALT1 that was active in-vetro and then screened a huge compound of chemicals to see if we could find certain chemical compounds that could disrupt MALT1 activity. That approach was successful in defining multiple chemical compounds. Then we focused on one compound and developed a family of compounds around it that were very active in inhibiting MALT1. There was one compound, which we dubbed for the time being MI-2 that actually binds and attaches to MALT1. So, it actually kills MALT1 completely. This particular inhibitor, MI-2, had very profound effects on killing lymphoma cells in experimental models, either in animal models lymphoma or taking primary human specimens and treating them outside of the humans.

You have only done this in mice so far?

Dr. Melnick: So far, it's in mice. We're working now with medicinal chemists to modify MI-2 so it can be given as a pill and at that point we'll apply for permission to test it in patients.

Would it be a pill a day?

Dr. Melnick: Yes, it probably would be a pill a day.

How long would they have to be on the medication?

Dr. Melnick: In the case of the lymphomas, they are basically very metabolically active so you can eradicate the lymphomas. In lymphomas, if they haven't come back within the space of five years they're very unlikely to come back.

Could MI2 be used to treat all the lymphomas, not just these hard to treat lymphomas? Could it mean you never use chemo or radiation again?

Dr. Melnick:  We think that we will be able to treat lymphoma patients without chemotherapy, but a single drug alone will not do the job. Tumors are complex; they have many molecular mechanisms that are disruptive and hitting a single one of those will not be sufficient to cure patients. So, for that purpose we are combining MALT1 with other drugs that we've created in the lab or from other drug companies based on what we know about the various different biological systems that control the cancer cells. You can then take drugs that hit those different components and hit them all at the same time. When you do that you really have amazing potency in wiping out tumor cells; it is remarkable. You can certainly cure all the animals' models very readily, which doesn't mean you can cure patients but actually it's when you are hitting multiple pathways at the same time. So, we're pretty confident that we will achieve a chemotherapy free cure. However, that's not the ultimate step. You have to first start with evaluating how these individual agents work alone; how they work with chemotherapy; whether they can be used to reduce the amount of chemotherapy that's given. Eventually, we will learn to combine them and will gradually take out the chemotherapy, step-by-step and eventually they won't need it.

Do you think something like this can be used on all cancers?

Dr. Melnick: There's a good chance that this could work for many cancer types. It's hard to be absolute and say all cancers. Cancer cells are machines and as we learn how they work, we can learn how to block their functions. So, it's reasonable to assume that we could fight many tumor types.

Are there any downsides to using this drug to target MALT 1 inhibitor?

Dr. Melnick: We don't know of downsides at the current time. For example, mice that don't have MALT1 are healthy so it looks like the lack of the protein is not lethal to another mammal. The first phase is always verifying the safety. It's a good sign when you know the protein you're targeting is not essential for life, because hitting it is unlikely to have a lethal effect. Sometimes other proteins can hit certain parts of it that are not required for life and leave the others intact. In the case of MALT1 we're inactivating its function, but we know that at least another mammal can live without it perfectly well. So, ideally I think that's the case. It's a fairly restrictive mechanism that plays a role in certain kinds of immune reactions. So temporarily suspending those is not necessarily expected to be toxic.

How long have you been working on therapies for lymphoma?

Dr. Melnick: Well, for the past twelve years.

Is this the closest you've come?

Dr. Melnick:  No. We have other drugs that are currently in the phase of being evaluated by the FDA to be used in humans. So, we have other experiences in making drugs that seem to be very promising as well. It's been doable to develop these. If you really study in depth these mechanisms, we can see what they look like physically. Once we know what all the elements are, then we can design very powerful drugs that inhibit those. It takes a lot of time, but when we get there the drugs are quite impressive and powerful.

Did something happen with technology that allows you to see this differently?

Dr. Melnick: Well, there are several ways that technology has enabled drug discovery. Obviously the human genome project defined what the genes are. It was a fundamental advance in modern medicine on its course. The other technology that has been important is the superior computational modeling. In the last few years, it has become more possible to model the configuration of proteins in the cells, which is extremely difficult. Those kinds of events have been very helpful for drug design and drug improvement. So, I would say the technology is booming.

So what's next?

Dr. Melnick: What's next is creating it into a pill form. So we can then apply for permission to treat patients with it and understand its role in therapy. We also are detailing exactly how we can combine it with chemotherapy and with other drugs because once we establish its safety then we would want to understand its role as a therapeutic agent in the context of currently administered drugs for lymphoma.

When you were working with the mice was there an "ah-ha" moment?

Dr. Melnick: There were several "ah-ha" moments. One of the very exciting parts of this project was the realization that the inhibitor we developed could basically attach and irreversibly inactivate MALT1, which is exciting because then it means that you really hit the target permanently. Protein turns over, but just giving a dose once a day is enough to keep all the protein off. Then, when we observed how profound the effect is against the tumors in the animal models or against the patient's specimens, we realized that this actually works. It actually has powerful effects against tumor cells.

FOR MORE INFORMATION, PLEASE CONTACT:

Lauren Woods
Senior Media Associate
Weill Cornell Medical College
(646) 317-7401
Law2014@med.cornell.edu

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