New Drug Stops Pediatric Cancer

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DIPG is the second most common brain tumor in kids. (KFSN)

DIPG is the second most common brain tumor in kids. The diagnosis is tough to deliver. It is almost always the same-little boys and girls are given less than two years to live. In fact, the median survival rate is only nine months and so far, there are no good treatment options. But doctors hope one family's sacrifice will change all of that!

"Jennifer was my baby girl," Tony Kranz, Jennifer's father told Ivanhoe. Libby Kranz, Jennifer's mother said, "she loved being a big sister."

Jennifer Kranz was full of life and love for her two brothers and baby sister. But her world came crashing down on her sixth birthday.

Libby told Ivanhoe, "I remember the doctor saying there is no cure."

A few days before, her parents noticed Jennifer's eye start to turn in. And within days, their seemingly healthy little girl was diagnosed with DIPG- a malignant tumor in the brain.

Michelle Monje, MD, PhD, Pediatric Neuro-Oncologist at Stanford University said, "It's a disease that we have been just absolutely terrible at treating. We've made no progress in extending the life of children with DIPG in over three and a half decades."

For Jennifer, the disease quickly ravaged her body.

"It's a cruel, terminal disease. They lose all their functions one by one, but they're always aware," Libby explained.

Jennifer survived just three-and-a-half months after her diagnosis. But what Jennifer and her parents did at the end of her life could end up saving others.

"The Kranz family donated Jennifer's tumor at the time of her passing, and it's one of the tumors that we study in our lab," Dr. Monje told Ivanhoe.

Dr. Monje says it was one of the tumors that was critically important in finding the first new drug that could extend life for these children.

"We slowed the growth of the tumors and we extended the survival time of the mice," she explained.

The drug, Panobinostat, was approved this year to treat adult blood cancer. Jennifer's tumors cells also allowed researchers to learn more about what this cancer does inside the body. A coalition of researchers world-wide is now working on new treatments.

Dr. Monje said this was really a beautiful example of team work in science, and a beautiful tribute to Jennifer. Her cells are still being used to help other children.

Libby told Ivanhoe, "Jennifer is still fighting this cancer and Jennifer will win one day. One day she will be part of the cure."

One little girl who may have lost the battle, but could help to defeat this cancer once and for all.

So far, the new drug has only been tested in mice. Researchers hope to begin a clinical trial this year. They know that it may not be a cure, but could add months, or even years to children who are fighting this deadly disease.


New Drug Stops Pediatric Cancer -- Research Summary


BACKGROUND: Diffuse Intrinsic Pontine Glioma, known as DIPG, is a highly aggressive brain tumor that accounts for 10 percent of all childhood central nervous system tumors. Each year about 300 children, typically aged five to nine, are diagnosed with DIPG. The tumor is a glioma which means it is a tumor that comes from the glial tissue, the brain support tissue that protects the neurons in the brain. Some of the most common symptoms of DIPG are double vision, inability to completely close the eye lids, drooping on one side of the face and difficulty chewing and swallowing. This tumor is one of the most resistant of all cancers to chemotherapy and tends to progress rapidly in the brain stem. (Source: http://www.danafarberbostonchildrens.org/conditions/brain-tumor/diffuse-pontine-glioma.aspx, http://www.thecurestartsnow.org/about/brain-cancer/dipg/)

TREATMENTS: Doctors will decide on a course of treatment based upon the child's health and age and the size and location of the tumor. By estimating the pace at which the tumor is growing, doctors can decide on which chemotherapy drugs to prescribe the patient. Some treatments include:

Radiation therapy: Traditionally prescribed upon diagnosis, high energy radiation rays are directed at the tumor to kill or damage the cancerous cells. Though more than 90 percent of patients have a response to the radiation, the results only last about six to nine months on average.

Chemotherapy: Some patients respond to chemotherapy but it is typically prescribed alongside radiation therapy.
Surgical removal of DIPG is considered dangerous since the tumor sits on the brain stem. Its location makes it difficult to remove without causing major neurological damage to the patient.

(Source: http://www.danafarberbostonchildrens.org/conditions/brain-tumor/diffuse-pontine-glioma.aspx, http://weillcornellbrainandspine.org/condition/diffuse-intrinsic-pontine-glioma-dipg)

NEW TECHNOLOGY: Michelle Monje, MD, PhD, Pediatric Neuro-Oncologist at Stanford University is using the tumor cells of Jennifer Kranz, who lost the battle to DIPG, in order to help other children with the disease. According to Dr. Monje, the median survival is only nine months and a five year survival is less than one percent. Unfortunately there has been no progress in the treatment of the disease for 35 years. Dr. Monje says one of the hardest parts about this cancer is that "You can't surgically remove it and you can only make the diagnosis on imaging alone. As a result there are very few tissue resources available for study." This is why Jennifer's tumor is so important. Now doctors are able to use Jennifer's and other children's tumors donated at the time of death to study and test what drugs might be affective. Because of this, researchers were able to test the drug Panobinostat that slowed the tumor growth and extended the survival time in mice. This could be the first step toward a cure for DIPG.

New Drug Stops Pediatric Cancer -- Doctor's In-depth Interview

Michelle Monje, M.D., Ph.D is a Pediatric Neuro-Oncologist at the Stanford Institute for Stem Cell Biology and Regenerative Medicine. She talks about how a newly FDA approved drug that is bringing hope to children suffering from DIPG.
Interview conducted by Ivanhoe Broadcast News in May 2015.


What is DIPG?

Dr. Monje: Diffuse intrinsic pontine glioma (DIPG) is a malignant cancer of childhood. It's the second most common malignant brain tumor in kids. It's a disease that affects approximately 300 children a year in the United States and it's the leading cause of brain tumor death in children. It is a disease that portends a terrible prognosis, the median survival is only nine months and the five-year survival is less than one percent.

What starts to go wrong? What are the signs?

Dr. Monje: This is a disease that comes on fairly rapidly. It typically strikes in mid-childhood peaking around age six and a half. In a previously completely healthy child you will first notice that one or both eyes is turning in and not looking straight ahead. This is quickly followed by a difficulty moving one or both sides of the face, then weakness on one or both sides of the body and tripping over your feet or bumping in to walls. Thereafter, a doctor visit usually results in an MRI scan and a diagnosis is made of DIPG.

Isn't the hard part about DIPG is you have to tell these parents you just found out your child has this and there's no cure?

Dr. Monje: It's a disease that we have been just absolutely terrible at treating. We've made no progress in extending the life of children with DIPG in over three and a half decades. The median survival prior to the initiation of radiotherapy was about six months and then when radiotherapy was introduced about 35 years ago, the median survival extended to about nine months. We have made no progress since that time despite quite a bit of effort in testing traditional chemotherapy drugs. There have been over two hundred clinical trials for children with DIPG in the last several decades but none of them have shown any benefit to survival.

Why do you think that is?

Dr. Monje: Part of it is that DIPG is a fairly unique disease biologically. Until very recently, we didn't have the resources in the laboratory to study it and to understand it. Part of why that's true is the inherent nature of the disease in that it diffusely infiltrates a critical part of the brain. Sort of like two colors of yarn knit together; you can't surgically remove it and you can make the diagnosis based on imagining alone. As a result, there are very few tissue resources available for study and until very recently we didn't know anything about the unique molecular biology of the disease. We didn't know what genes were mutated. We didn't have a cell culture in the laboratory to test new drugs or an animal model to study possibly effective new drugs that could extend survival. We were really operating in the dark. And in the last five to six years that black box has been opened.

I've done a lot of stories on glioblastomas. Is this a lot like that where it has fingers and it goes out into the brain?

Dr. Monje: Absolutely. Under the microscope this disease looks a lot like adult glioblastoma. We now know that it's a unique disease. It is biologically quite distinct from adult glioblastoma but it has the same set of problems in that it diffusely infiltrates. It doesn't just infiltrate the brain stem where it originates. We now understand that it spreads far and wide in the nervous system of the child. This is a disease that we really have difficulty treating not only because we can't surgically resect it, but because our hands are tied in terms of the kinds of therapies that we currently have and what we can deliver to the tumor cells.

What's so nice about this new old drug? Your hands are untied a little bit because this drug is already FDA approved.

Dr. Monje: This new old drug might be a useful therapy for DIPG. In the last few years incredibly generous patients and patient families have donated their tumors at the time of the child's death. That has allowed us to establish cell cultures of the tumor. We now have cell cultures with which we can test what drugs might be effective against DIPG. These incredibly generous tissue donations are meant to help future children with DIPG. They have helped scientists uncover the molecular biology of the disease. We now understand quite a bit about what's going wrong in these tumor cells and what might be effective ways to treat them.

What's going wrong in DIPG?

Dr. Monje: DIPG tumors have a very specific mutation in one gene that results in the dysregulation of thousands of genes. This is a mutation that effects epigenetic regulation, the way that genes are expressed. Even though there's just one little thing wrong with the DNA, it's in the right place at the right time to unleash a cascade of bad events within the cell. As we're starting to better understand that, we're realizing that drugs that target epigenetic regulation, the way that the genome gets expressed, represent a promising therapeutic strategy for DIPG. This is likely to be the most effective strategy because that is really what is wrong with the tumor cell. Understanding that, and having these invaluable patient-derived cellular resources to test new therapies is how a coalition of researchers throughout the world got together. All scientists who had DIPG cells to study got together and decided to put our resources together. We put our heads together and tried to systematically find an effective therapy for children with DIPG. Putting those tissue resources together, we were able to screen a total of 16 DIPG cell cultures against a panel of drugs that we thought might be effective therapies. Most of these drugs were newer, more targeted agents. This panel of drugs included agents that specifically target the epigenome like the new drug panobinostat. In screening them, what we found that there were very few drugs that were effective against this tumor. That was consistent with what we know to be true about the tumor in children; that it's very hard to treat. The drugs that rose to the top were the epigenetic targeting agents. There was one in particular that was very potent and seemed to be effective against the majority of the cell lines that we tested. When we went and tested whether it did in fact extend survival in mouse models, we found hopeful results that there was some beneficial effect. So we're now in the process of bringing this to clinical trial for kids with DIPG and we hope that it will be similarly effective in children battling this disease.

How many people around the world research DIPG?

Dr. Monje: There were 13 different institutions that were on this collaborative project. The final author list names the senior researchers together with the students and post-doctoral fellows that worked on this project. There were a total of 40 individuals. It was a big team effort. This was really a beautiful example of team work in science. Everybody was working towards this common goal of finding an effective therapy and understanding why it was effective so we could really make a step forward for kids with DIPG.

What is the drug FDA approved for?

Dr. Monje: The drug is called panobinostat and it's made by the company Novartis. It is a drug that's recently been FDA approved for a hematologic cancer called multiple myeloma. It's a drug that inhibits what are called histone deacetylases. The drug is a histone deacetylase inhibitor (HDACIs). Histone deacetylase are enzymes that are responsible for taking acetyl groups off of a protein called a histone. The histones are kind of like the spools that DNA gets wrapped around as DNA gets packaged into chromatin. That mutation that I mentioned occurs in about 80 percent of DIPG tumors is a histone mutation. That mutation results in the inability of the cell to tag the histones in a particular way that helps to control gene expression. In particular, the ability of the cells to put methyl groups on a particular place in the histone. The histone deacetylase inhibitor helps to restore that function within the cell.

Multiple myeloma and a brain tumor are completely different things?

Dr. Monje: Multiple myeloma and a brain tumor are cancers that come from different cells. Targeting epigenetic regulation is effective in both kinds of cancers and I think that targeting epigenetic regulation of gene expression is going to emerge as a strategy that's effective for numerous cancers.

How many did it help, what was the percentage that you saw?

Dr. Monje: What we saw with the mouse studies is this drug slowed tumor growth and it extended survival in DIPG tumor-bearing mice for a matter of several days to a couple of weeks in the mice.

What do you mean extended survival?

Dr. Monje: When we treated mice with the drug panobinostat, we slowed the growth of the tumors and we extended the survival time of the mice. But it's important to note that we didn't cure these mice. Even in a Petri dish when we treated tumor cells with panobinostat, we saw that there were some tumor cells that developed resistance to the drug. We don't believe that this drug alone is going to be a cure for DIPG. What we hope is that it extends life and extends quality of life for children with DIPG hopefully by some matter of months. We still have quite a bit of work to do and we hope that this is a first step forward.

How important is it that this drug is already FDA approved, how will that change life for you going forward?

Dr. Monje: It's wonderful that panobinostat is FDA approved. We're preparing to open a Phase I clinical trial to test the safety of panobinostat in children with DIPG and to find the maximum tolerated dose. Once that first Phase I clinical trial is complete, then we hope to move forward toward the Phase II clinical trial to test for the efficacy of this drug in children with DIPG. I hope this is going to be a step forward. I hope that this drug will prove to extend life by some matter of months, but I know that we still have quite a bit of work to do and that this is only the first step forward.

How did Jennifer, Tony and her mom Libby play a role in this study?


Dr. Monje:
The Kranz family has been enormously supportive of DIPG research and they've played multiple roles in supporting research on this tumor for future children who are struck by this disease. The Kranz family donated Jennifer's tumor at the time of her passing and it's one of the tumors that we study in our lab. It's one of the tumors that was critically important in this study that discovered the potential of this drug panobinostat. In addition, they continue to support our research financially. They do a great deal of fundraising and are always looking to support research for DIPG.

Was Jennifer's tumor one that found this drug would possibly help?

Dr. Monje: Jennifer's tumor was one of the tumors that we studied. In this particular study of panobinostat, it was one of the tumors that we relied on heavily as we dug in to what the mechanism might be of this drug within the context of DIPG.

How important is it for Jennifer's parents to move forward and even though they can't help Jennifer, their passion now is to help others?

Dr. Monje: This disease comes on quickly and it quickly progresses. It's astounding to me that people come to the decision to donate tumor tissue within that incredibly rapid time frame. It's an enormously selfless thing to think about future children affected by this disease while you're still coming to terms with your own child's diagnosis. It's really a beautiful example of human nature and I think the Kranz family has done quite a lot to help future children in honor of Jennifer.

In the video Libby promises to take care of her other surviving children. Is it common that siblings would get this?

Dr. Monje: DIPG is a disease that, as far as we can tell, as far as we understand, appears to strike somewhat at random. There are not genetic predisposition syndromes for DIPG. There are not well understood environmental risk factors and there's nothing that parents have done or didn't do that brought this disease on for their children. Siblings do not appear to be at any increased risk at developing the disease.

Do you work with patients as well as research? Does that make it even more meaningful for you?

Dr. Monje: Absolutely. I'm motivated to do what I do in the lab because I see patients who are affected by DIPG and I can't help them... but I desperately want to help them. Balancing clinical practice with research is the only way that I feel I can move us forward.

If you would like more information, please contact:

Michelle Monje, M.D., Ph.D

(605)736-0885

mmonje@stanford.edu
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