PHOTOS 2014 Sarcoma Symposium Nancy’s Promise Newsletter of the University af Iowa Holden Cancer Center Melanoma and Sarcoma Tissue Bank

Since 2008, the melanoma IN THIS ISSUE and sarcoma programs at the University of Iowa have been rapidly growing. We have two strong teams in Foreword both programs with highly page 2 specialized scientists Michael Henry, Ben Miller and Mo Milhem and physicians who are Patient Profiles dedicated to these fields. Melanoma Symposium pages 3-5 These teams have led and opened numerous clinical trials which have enhanced Patient Advocates research in both diseases. page 5 One of the most important resources to transpire is the MAST (Melanoma And Sarcoma Tissue bank). The MAST is a repository of new or Mast Poster previously diagnosed patients with proliferative disorders of the skin, ocular or pages 6-7 connective tissue disorders. The purpose of the MAST is to generate a comprehensive bank with biospecimen and clinical information that will contribute to the success of many multidisciplinary and translational research projects at the University of Iowa. Social Media By the Numbers pages 8-9 This is our first publication for you to meet the team at the University of Iowa for both (Follow us!) disease types, learn about initiatives, collaborations, new research ideas and patient stories. Research Groups page 10 The MAST is possible thanks to the generosity of grateful donors who support our 2013 Facebook: work and trust in our expertise to further research in these two diseases. Sarcoma Iowa Grant Recipients Melanoma Iowa pages 11-12

Mohammed M. Milhem, MD Twitter: Photos Deputy Director for Clinical Cancer Services pages 13-16 Holden Comprehensive Cancer Center @SarcomaIowa University of Iowa @MelanomaIowa

Blog: ISSUE NUMBER 1 www.doctormoiowa.com 2014 Fall/Winter 2014

16 MAST Newsletter their way to do things for me much more than they needed to. I am so grateful for them and what they did for me during this time, and during my whole fight. I primarily spent this time Foreword going back and forth between my apartment in Iowa City and Patient Profiles my parents’ houses in Cedar Rapids, when I was not at UIHC Nancy White for treatments. This was an uneventful time, to say the least. My days were filled with watching movies, Netflix, and playing videogames. It was the lazy time you fantasize about when you We discovered Care Pages at the University and that became Nikolas Jiruska – Ewing’s Sarcoma the cancer had spread anywhere else. After the initial blow are living a normal, busy life, but believe me when I say this very important therapy for Jim. He would write about his from this horrifying diagnosis, we only received good news lifestyle gets old very fast. thoughts and feelings on this new, unexpected journey in life. from then on. All of the tests revealed that the cancer was After beating five video games and watching countless movies All the inspiring responses he received back meant so much to localized in my hip and had not spread to the brain, lungs, or and TV shows, my three-month appointment with Dr. Miller him and helped him keep up the fight. bone marrow, which are three locations that this could likely arrived on November 14th and he gave me the OK to start spread to. bearing weight on my left leg. Goodbye, walker and crutches. I Through it all, Jim had a passionate doctor fighting right along started practicing to walk immediately when I got back to my his and his family’s side…Dr. Mo. Jim felt that the Holden At this point, I started my chemotherapy treatments and talked apartment after that appointment. It was an awkward and Cancer Center was the right place for him to be during his with my oncologist, Dr. Mohammed Milhem (just “Mo” for exciting feeling. I had, and still have, an overwhelming feeling battle. The U of I Hospital became a second home for us for every one who knows him), to get an idea of what the next few of thankfulness that I have the opportunity to walk, because over a year. It was not as overwhelming as we thought it might months would entail. I would receive chemotherapy not everyone is fortunate enough to be able to keep their limb be, as the doctors and their teams worked together as one unit, treatments every two weeks, alternating between two and when they are diagnosed with Ewing’s Sarcoma. deciding on what was the best treatment for Jim though many five-day treatments. I would have five rounds of chemotherapy changes in his condition. They kept us and the family informed and then have more scans to see how it reacted to the At this point, life was getting pretty good. I was walking again on everything going on so we could make the best decisions we treatment. Shortly after, Dr. Benjamin Miller would perform and only had four more chemotherapy treatments to go. need for Jim. surgery to remove the tumor. We thought I would have to However, my last few treatments were delayed because I was receive a hip replacement, but there was a chance I could also really feeling the negative effects of the chemotherapy and I Jim passed away March 23rd, 2011. Even though Jim could not My name is Nikolas Jiruska and I recently finished receiving have a bone allograft surgery depending on how the tumor was not meeting the required blood counts to be able to start win his fight against Melanoma, it was his hope that others chemotherapy treatments to fight a rare form of bone cancer reacted to the treatment. After the surgery, I would go on to the next round of treatment. I had to receive a handful of could learn from his struggle. Jim wanted to use the lesson called Ewing’s Sarcoma. This disease primarily affects children receive nine more rounds of chemotherapy for 18 weeks. blood transfusions during this time to help meet the blood learned from how his body reacted to the disease in effort to and adolescents, but I was diagnosed at the age of 20. It was a count requirements. Thinking about it now, these setbacks support the doctor’s and research teams when it comes to long journey, and I am fortunate enough to be able to say that It took me a few rounds of chemotherapy before I started to were not a big deal at all compared to what can happen when gathering data needed from his tissue samples, blood and how I am now back at The University of Iowa nine months later feel the effects. One of the effects that was the most difficult receiving chemotherapy treatments. At the time, though, it the cancer moved through his body. He knew towards the end and enjoying life more than ever. Now, let’s go back to April for me to grapple with was losing my hair. It was sort of my seemed awful because I was so anxious to finish and get on that new findings would probably not benefit him directly, but 2013 where my journey began. trademark and was a big adjustment in my life. However, a with my life. wanted others with this horrible disease to be able to win this small price to pay, considering it would grow back eventually. Finally, January 3rd came around and it was time to go in for fight and have a chance to enjoy a life after a melanoma I started feeling pain in my left hip towards the end of April. It Some of the other side effects I felt throughout my treatments my final chemotherapy treatment. Unfortunately, this had to diagnosis, as well as bringing awareness to others about was a fairly mild pain and it would come and go every so often. were lightheadedness, fatigue, and nausea. be a five-day treatment. The longest five days of my entire life, preventing this disease. I thought it might have been a pulled muscle or a pinched I think. My girlfriend stayed with me every night in the nerve. This persisted for a few weeks before the pain started to The first five treatments flew by much faster than I had hospital, as she did during my treatments in the summer My husband Jim White had been diagnosed with melanoma in So to make Jim’s wish a reality his family decided to donate get worse. Fortunately, the intense pain waited until I was done anticipated, and all of the sudden it was August. I had my scans months, which made everything a lot more bearable because 1999. We did not know that much about melanoma at that funds from The Jim White Foundation that was created shortly with my final exams for the spring 2013 semester. I went to the and my cancer had reacted very well to the chemotherapy she is a very comforting person to be around. The wonderful time. All we knew at the time was that Jim had a funny looking after his passing. These funds were given to the tissue and emergency room at St. Luke’s Hospital in Cedar Rapids the treatments, shrinking the tumor a lot. Dr. Miller determined nurses of 4JPE in UIHC presented me a beautiful cookie cake mole on his shoulder that they had to remove. It was stage II blood bank for Melanoma patients at the Holden Comprehen- first time the pain in my leg became unbearable. It started in that I would be able to have the bone allograft surgery. There to congratulate me on my final day. I then returned to Cedar and after the removal he was told that everything looked clear. sive Cancer Center. There they can learn more about my hip and would send deep, pulsing pain down my entire leg. is a longer recovery time with this route, but long-term, it Rapids for a couple of weeks of rest, relaxation, and relief During the next 11 years he would be checked at his physicals melanoma’s effects on the body and how to develop new They drew blood and took X-rays of my back and hip, but were would be better for my leg in terms of returning to normal before I would return to school. I returned to UIHC three routinely, but we went on with our lives and looked at this treatments, and provide more hope to future patients and their not able to draw any conclusions from this work. I received functionality. Dr. Miller and his team performed a successful weeks after I completed chemotherapy for a bone scan and CT simply as Jim was a cancer survivor that had caught this in families. some pain medicine and was told to keep monitoring my leg. surgery to remove my tumor on August 21st. He determined plenty of time to live a long and normal life. We had no idea scan to make sure I was clean. Sure enough, the scans were that 95% of the tumor was dead and had been removed with clear. We were all optimistic that this would be the case, and it what melanoma was capable of. With Jim’s passing a large part of me is missing. Things we The pain continued to grow worse and worse from then and I clean margins. This was a big step out of the way, and every- was truly a wonderful feeling. Time to get back to life. thought we would experience together are no longer a reality. went to the emergency room two more times before I finally thing was downhill after that. Then in 2010, Jim had a cough and went to his doctor, who Now it is my retirement, not ours. received an MRI. The ER doctor who was tending to me knew I am sitting here writing this now and I do not feel bitter about after some tests referred him to the University of Iowa Hospital immediately that I had cancer after looking at the results of Perhaps it is only at this point in time that I can say that it was having to have endured this experience at all. I have only to be and Clinics. In late Feb on our wedding anniversary we found We were looking forward to spending a lot of time with our the MRI. This was the last thing I ever expected to hear, downhill after surgery. At the time, life was very difficult. I was thankful that I survived it. Also, as odd as it may sound, I am out Jim had recurrent melanoma, but this time it was in his grandchildren and present for their activities and cheering especially at age 20. The doctor arranged for me to go to The not able to put weight on my left leg for three months because sort of thankful that I went through this experience because I bronchial area and was very serious. them on. Now I will have to be there without Jim. University of Iowa Hospital and Clinics immediately. My my bone had to heal around the graft, and when you are learned a lot about myself during this time and it strengthened parents, girlfriend, and I left St. Luke’s and went straight to dealing with healing bone, everyone knows this is a very slow my relationships with those closest to me. I want to conclude So the fight began. We were a team though all of his struggles I went to a soccer game recently for one of our grandsons and Iowa City in the middle of the night. process. This lack of mobility along with starting my final nine my story by saying that you should never overlook any pain or to beat melanoma. He knew I was there to pick up the fight as we were leaving for the game he said, “I wish grandpa could rounds of chemotherapy made my choice to withdraw from odd feeling you may experience in your body. I did not do this when he had a rough day, and reached his weakest points, and be here to go to my game.” That tore at my heart. After a few days of various tests, I was officially diagnosed with school for the fall 2013 semester pretty easy. and the early detection of my cancer may have saved my life. I that he was never alone in the fight. We could not fight this So this is what Jim and his family do not want for other families. Ewing’s Sarcoma on June 4th, which also happens to be my also want to give thanks to my wonderful caregivers through- alone. Family members and friends kept us going in difficult Our wish for them is to win their fight against melanoma and mother’s birthday (happy birthday, right?). Although we had I do not know how I would have made it through those three out this journey, including Mo, Dr. Miller, my parents, my times, and there were many. be able to share in those special moments in life together. the official diagnosis, there was still a lot to do to find out if months without my parents and girlfriend. They went out of girlfriend, and the nurses of 4JPE, 4JPW, and 2RCW.

2 MAST Newsletter Fall/Winter 2014 3 PATIENT PROFILES

their way to do things for me much more than they needed to. Fletcher Summa – Sarcoma Gilles Cochet – Melanoma his life fighting cancer and finally lost his battle a few years ago. I am so grateful for them and what they did for me during this My mother also fought cancer but was able to fight her way time, and during my whole fight. I primarily spent this time through it. To tell the truth, I was expecting to have cancer one going back and forth between my apartment in Iowa City and day but, so soon? my parents’ houses in Cedar Rapids, when I was not at UIHC Thanks to the support of my wonderful wife, I learned to accept for treatments. This was an uneventful time, to say the least. this diagnosis. After the surgery and the removal of the My days were filled with watching movies, Netflix, and playing lymphatic system in my right arm (where the cancer had videogames. It was the lazy time you fantasize about when you spread), I was sent to the Holden Comprehensive Cancer Center Nikolas Jiruska – Ewing’s Sarcoma the cancer had spread anywhere else. After the initial blow are living a normal, busy life, but believe me when I say this at the University of Iowa Hospital and Clinics to start a clinical from this horrifying diagnosis, we only received good news lifestyle gets old very fast. trial of ipilimumab with Dr. Mohammed Milhem. The descrip- from then on. All of the tests revealed that the cancer was tion of the potential side effects was pretty scary but we decided After beating five video games and watching countless movies to think positively and look on the bright side. No matter what localized in my hip and had not spread to the brain, lungs, or and TV shows, my three-month appointment with Dr. Miller the result, my participation would help research and other bone marrow, which are three locations that this could likely arrived on November 14th and he gave me the OK to start I am a French engineer living in Cedar Rapids. I was sent here people. I thought a lot about my family during this time and spread to. bearing weight on my left leg. Goodbye, walker and crutches. I four years ago to work on a 10 month mission and never left. My before I knew it, I was through with the first phase of treatment started practicing to walk immediately when I got back to my family and I enjoyed the life here so much that we decided to and I handled it pretty well- actually, very well. At this point, I started my chemotherapy treatments and talked apartment after that appointment. It was an awkward and grasp the opportunity that life offered us here in Iowa. with my oncologist, Dr. Mohammed Milhem (just “Mo” for The summer of 2012 was the first time our family took a vacation Today, I am still afraid every time I go to the hospital but I know exciting feeling. I had, and still have, an overwhelming feeling the place is full of incredible nice people. I still have a few every one who knows him), to get an idea of what the next few In January of 2012 after shoveling my driveway, I experienced in the U.S. and upon return home, I noticed a mole on my of thankfulness that I have the opportunity to walk, because shoulder that began to change and grow. When I finally decided infusions to go through but they are spaced out enough to give months would entail. I would receive chemotherapy not everyone is fortunate enough to be able to keep their limb significant pain in both of my knees. We have a big driveway my body some time to deal with the product. treatments every two weeks, alternating between two and to go see my physician, she sent me right away to a local surgical when they are diagnosed with Ewing’s Sarcoma. so I didn’t think much of my soreness. After a few days of oncologist. When the results of the biopsy came back and I was Recently, I was given the opportunity to acquire an old 1974 five-day treatments. I would have five rounds of chemotherapy pain, my left knee began to feel better but my right knee and then have more scans to see how it reacted to the At this point, life was getting pretty good. I was walking again told that I have melanoma, I passed out. My brain simply Corvette so I grabbed it! It’s a little boys dream to have a remained sore. I continued to wrap it for what ended up couldn’t process this diagnosis. My father spent a good part of Corvette- life is good! treatment. Shortly after, Dr. Benjamin Miller would perform and only had four more chemotherapy treatments to go. being two months. The pain did not subside, in fact it got surgery to remove the tumor. We thought I would have to However, my last few treatments were delayed because I was receive a hip replacement, but there was a chance I could also really feeling the negative effects of the chemotherapy and I worse. I finally asked my mom to schedule a doctor’s appoint- My name is Nikolas Jiruska and I recently finished receiving have a bone allograft surgery depending on how the tumor was not meeting the required blood counts to be able to start ment to see what could be done. I explained the soreness to Patient Advocates chemotherapy treatments to fight a rare form of bone cancer reacted to the treatment. After the surgery, I would go on to the next round of treatment. I had to receive a handful of the doctor and we decided that my knee was just inflamed. When I was asked to be a patient called Ewing’s Sarcoma. This disease primarily affects children receive nine more rounds of chemotherapy for 18 weeks. blood transfusions during this time to help meet the blood Luckily, as he was heading out the door, I added that a bone My name is Molly (First) McDowell, the sister of Hannah First. Hannah was only 10 advocate by my father's doctor, Mo, I and adolescents, but I was diagnosed at the age of 20. It was a count requirements. Thinking about it now, these setbacks by my knee also ached. He sent me to get an x-ray. In a week I years old when she was diagnosed with It took me a few rounds of chemotherapy before I started to were not a big deal at all compared to what can happen when would learn that that decision may have saved my life. I was was overwhelmed with many emotions. long journey, and I am fortunate enough to be able to say that osteosarcoma. Hannah battled many receiving chemotherapy treatments. At the time, though, it My father, Jim, passed away from I am now back at The University of Iowa nine months later feel the effects. One of the effects that was the most difficult called into his office urgently the next week. He showed me remissions of the disease for 10 years until and enjoying life more than ever. Now, let’s go back to April for me to grapple with was losing my hair. It was sort of my seemed awful because I was so anxious to finish and get on and my mom an x-ray and pointed to an oddly shaped array melanoma back in March of 2011. My it took her life at the age of 19 in March initial thought was “why choose me?”, as 2013 where my journey began. trademark and was a big adjustment in my life. However, a with my life. known as a ‘sunburst’ (named after its resemblance to a solar 2013. Hannah was my everything. She I did not personally battle cancer and I small price to pay, considering it would grow back eventually. flare from the sun). A ‘sunburst’ is an indicator of osteosar- introduced me to my amazing husband, Finally, January 3rd came around and it was time to go in for know nothing of medicine or the kinds I started feeling pain in my left hip towards the end of April. It Some of the other side effects I felt throughout my treatments coma, an aggressive bone cancer. and we were able to be married in her my final chemotherapy treatment. Unfortunately, this had to of decisions that doctors have to make was a fairly mild pain and it would come and go every so often. were lightheadedness, fatigue, and nausea. be a five-day treatment. The longest five days of my entire life, hospital room a month before her passing. Molly McDowell She continues to live through me every day Jay White each day. But Dr. Mo encouraged me. I thought it might have been a pulled muscle or a pinched I think. My girlfriend stayed with me every night in the After an MRI confirmed my diagnosis, I was sent to the and will forever be my hero. Since her And over dinner said something I will nerve. This persisted for a few weeks before the pain started to The first five treatments flew by much faster than I had hospital, as she did during my treatments in the summer University of Iowa Hospitals and Clinicis in Iowa City. There I passing, I have completely devoted my life to spreading awareness never forget. "Do not overthink this, get out of your own get worse. Fortunately, the intense pain waited until I was done anticipated, and all of the sudden it was August. I had my scans months, which made everything a lot more bearable because met Dr. Mohammed “Mo” Milhem. He was not like any for sarcoma research and funding. In the last year, I have become head and simply be engaged in the moment". That was in with my final exams for the spring 2013 semester. I went to the and my cancer had reacted very well to the chemotherapy she is a very comforting person to be around. The wonderful doctor I’d ever met before. He was animated and funny, yet an active member of the Courage Ride, which is an annual bike response to me asking “what is my main responsibility as a emergency room at St. Luke’s Hospital in Cedar Rapids the treatments, shrinking the tumor a lot. Dr. Miller determined nurses of 4JPE in UIHC presented me a beautiful cookie cake very matter of fact. I would learn that his attitude was the ride in honor of a young man who passed away from a sarcoma. patient advocate?” first time the pain in my leg became unbearable. It started in that I would be able to have the bone allograft surgery. There to congratulate me on my final day. I then returned to Cedar my hip and would send deep, pulsing pain down my entire leg. is a longer recovery time with this route, but long-term, it right one. There was no time to dwell in the negative, and All of the funds from the Courage Ride go to the University of Rapids for a couple of weeks of rest, relaxation, and relief Iowa Holden Comprehensive Cancer Center (HCCC) towards They drew blood and took X-rays of my back and hip, but were would be better for my leg in terms of returning to normal there was also no need to worry, for he had a plan to cure He has encouraged me to listen, and ask questions that before I would return to school. I returned to UIHC three sarcoma research. For the 2014 Courage Ride, I am in charge of functionality. Dr. Miller and his team performed a successful me. The treatment was intense. Within a week or so of my not able to draw any conclusions from this work. I received weeks after I completed chemotherapy for a bone scan and CT collecting donations for and organizing the silent auction. This is challenge others, no matter where they might be in their some pain medicine and was told to keep monitoring my leg. surgery to remove my tumor on August 21st. He determined scan to make sure I was clean. Sure enough, the scans were diagnosis I was hooked up to bags of chemo, staying in the a very rewarding experience for me because I know all of the hard profession. It was made clear to me that I have a unique that 95% of the tumor was dead and had been removed with clear. We were all optimistic that this would be the case, and it hospital for 3-5 days at a time. My life had been flipped work that I put into gathering donations will help destroy the perspective of watching someone very close to me fight this The pain continued to grow worse and worse from then and I clean margins. This was a big step out of the way, and every- upside down. The thing that kept me upbeat was the support disease that took my sister from me. disease and lose their life doing so. So if I can represent the was truly a wonderful feeling. Time to get back to life. went to the emergency room two more times before I finally thing was downhill after that. I got from friends, family, and the wonderful staff of nurses families of the patients that struggle to understand their received an MRI. The ER doctor who was tending to me knew I am sitting here writing this now and I do not feel bitter about This year, not only am I helping with organizing the silent and doctors. I would get to know the staff very well. I couldn’t auction, I am also planning to raise $10,000 to shave my head at loved one's options, or have to make the tough call when the immediately that I had cancer after looking at the results of Perhaps it is only at this point in time that I can say that it was having to have endured this experience at all. I have only to be imagine making it through the long days, painful procedures, the Courage Ride! The best part of it all is that Dr. Mo from the person dealing with cancer cannot, then maybe I can play a downhill after surgery. At the time, life was very difficult. I was thankful that I survived it. Also, as odd as it may sound, I am the MRI. This was the last thing I ever expected to hear, and other obstacles I faced without them. I was so used to HCCC will be the one to shave it for me! This is going to be such small role in helping others beat this horrible disease. I am especially at age 20. The doctor arranged for me to go to The not able to put weight on my left leg for three months because sort of thankful that I went through this experience because I going to get treated that once I was finally done it felt like my an exciting, amazing experience for me. I love that I can do honored to be a part of such an amazing movement that is University of Iowa Hospital and Clinics immediately. My my bone had to heal around the graft, and when you are learned a lot about myself during this time and it strengthened world was flipped upside down another time. I’m very something like this in Hannah's honor. I know for sure that she is taking place at the Holden Comprehensive Cancer Center at parents, girlfriend, and I left St. Luke’s and went straight to dealing with healing bone, everyone knows this is a very slow my relationships with those closest to me. I want to conclude grateful for that. I can now have a life outside of a hospital cheering me on right now. Doing such an amazing thing makes the University of Iowa Hospitals and Clinics. Iowa City in the middle of the night. process. This lack of mobility along with starting my final nine my story by saying that you should never overlook any pain or me wish that I could shave my head every year! I plan to stay rounds of chemotherapy made my choice to withdraw from odd feeling you may experience in your body. I did not do this and begin to pursue whatever I want. I’m a much stronger incredibly active with the Courage Ride and spread sarcoma After a few days of various tests, I was officially diagnosed with school for the fall 2013 semester pretty easy. and the early detection of my cancer may have saved my life. I person now than I was before getting sick, and I appreciate awareness in any way that I can. I am very excited to make a major Ewing’s Sarcoma on June 4th, which also happens to be my also want to give thanks to my wonderful caregivers through- the world around me far more. difference in the world. I know that it is something Hannah mother’s birthday (happy birthday, right?). Although we had I do not know how I would have made it through those three out this journey, including Mo, Dr. Miller, my parents, my would have done if she was here. I have to fight sarcoma just as the official diagnosis, there was still a lot to do to find out if months without my parents and girlfriend. They went out of girlfriend, and the nurses of 4JPE, 4JPW, and 2RCW. she did while she was here. It is my turn to be the strong one.

4 MAST Newsletter Fall/Winter 2014 5 Tina Knutson BA, Laura Jacobus MS CCRC, Helen Pope BA, Carl Sohocki BA, Aaron Bossler MD PhD, Ocular, Skin and Connective Tissue Clinical Data Peter Nagy MD PhD, Mohammed Milhem MBBS – Univ. of Iowa Hospitals and Clinics, Iowa City, Iowa and Tissue Sample Collection Project (MAST) * Supported by UI Foundation & UI Clinical Trials Support Core

ABSTRACT ELIGIBILITY Table 2. Survival of Enrolled MAST patients per Subtype BIOSPECIMEN DATA REVIEW Table 6. Percent collection The primary purpose of the MAST study is to develop and maintain a repository of Major Inclusion Criteria Enrolled Melanoma Subtypes Alive CTB Total Table 5. Serum and DNA samples collected of total enrolled new or previously diagnosed patients with proliferative disorders of skin, ocular and ■ Male or female patients aged 18 years old with a proliferative disorder of skin or ≥ Acral Lentginous Melanoma 7 2 9 connective tissue disorders. MAST was initiated in April 2008, IRB approval was ocular tissue are eligible for full participation in the study. Serum total: 624 DNA total: 234 % Population collected obtained in July 2008 and first patient enrolled in October 2008. Enrollment is Amelanotic Melanoma 4 4 ongoing and will continue until a patient expires or withdraws from the study. ■ Male or female patients aged < 17 years old with a proliferative disorder of skin or Mid Tx 36% DNA - PB 211 Patients enrolled 402 ocular tissue are eligible for limited participation in the study with parental consent. Desmoplastic Melanoma 11 3 14 A main goal of this project is to generate a comprehensive bank that will contribute to Post Tx 21% DNA - Tissue 23 Serum samples 63% the success of many multidisciplinary and translational research projects. There are ■ Must allow storage of data, tissue and specimens for future research Lentigo Maligna Melanoma 13 4 17 Post Excision 20% ■ PB DNA average is DNA - PB 42% not specific research questions proposed; but rather created to build a repository of Major Exclusion Criteria Malignant Melanoma, NOS 68 27 95 biospecimen and corresponding clinical information that will prove invaluable as *Pre Tx 19% 393 ug. DNA - Tissue 6% ■ Does not allow prisoners to be subjects investigators within the institution generate further research questions. Metastatic Melanoma 19 23 42 ■ Tissue DNA average is Other 3% 315ug. ■ 256 Unique Serum MM, Malignant Blue Nevus 1 1 2 As part of the Biospecimen repository, serum and DNA are collected from peripheral STUDY DETAILS *Pre Excision 1% ■ Primary tissue difficult to samples blood samples on all returning patients. Tissue samples are collected on patients Mucosal Melanoma 5 5 collect due to small size ■ 171 Unique PB-DNA ■ Weekly screening of physician and surgeon clinic lists to determine eligibility and identified having a surgical procedure at UIHC. The tissue samples are flash frozen Post- samples can often ■ Sentinel lymph node samples sample collection Nodular Melanoma 57 14 71 and allocated for DNA, RNA, IHC and HE processing. Several UIHC services provide a be used as *Pre- samples biopsies hinder collections ■ PB - DNA collection was and is not reflected in the key role in the success of our sample collection process. These include: Tissue ■ Consent all subtypes of Melanoma and Proliferative Tissue Disorder diagnosis Ocular Melanoma, Chorodial 23 4 27 due to high amount initiated in March 2011 Procurement Core, Molecular Pathology and Histology Research Laboratories. above data. Tx: treatment. radioactivity present ■ Abstract subject medical records for Clinical information: Ocular Melanoma, Ciliary Body 2 1 3 Clinical data collection includes pathological diagnostic details (subtype, anatomical – Demographic Ocular Melanoma, Iris 2 STUDY OVERVIEW & MODIFICATIONS site, size, labs, BMI, etc), corresponding treatment intervention (primary, adjuvant and – Treatments 2 ■ Initial MAST study IRB approval received in July 2008. metastatic), past medical and family histories, environmental exposure assessment, – Co-morbidities Ocular Melanoma, NOS 3 3 bi-annual comorbidity follow up and annual standardized quality of life assessments. ■ IRB approval for minor study modifications and tissue procurement received – Environmental exposures Other 2 2 October 2008. Tissue collection limited to pilot of only 5 specimens. We would like to report on over 390 Melanoma patients currently enrolled in the – Clinical lab values MAST study. This review will include a clinical and biospecimen data review using Spindle Cell Melanoma NOS 1 1 2 ■ First patient enrolled in November 2008. Initial enrollment limited to Dr. Milhem’s – Pathological details UIHC Oncology Clinic. data points mentioned above. Notes on obstacles overcome and future goals will also Superficial Spreading Melanoma 84 20 104 be included. This study is funded by Holden Comprehensive Cancer Center Clinical ■ Conduct participant follow up every six months to update clinical and Quality of Life ■ Expanded patient enrollment to other UIHC Oncology Physician Clinics. Trial Support Core and The University of Iowa Foundation. (QOL) information. A standardized subject reported QOL survey is provided annually Total 302 100 402 ■ Approval received in March 2009 from UIHC Pathology Dept to collect additional and includes physical, social, emotional and functional well-being details. Tissue samples ■ Maintain clinical registry and specimen databases Malignant melanoma , NOS (55%); Metastatic melanoma (28%), Nodular melanoma (20%) ■ Expanded patient enrollment to UIHC Oncology Surgical Clinics. BACKGROUND and Superficial Spreading melanoma (19%) have the highest mortality rates of those ■ Enlisted UIHC Tissue Procurement to collect “extra tissue” for MAST in November ■ In Iowa alone, approximately 550 cases of Melanoma were diagnosed last year, subtypes with more than 40 patients enrolled. MM: malignant melanoma; NOS: not 2009. within the national average. CLINICAL DATA REVIEW otherwise specified; CTB: cease to breath ■ Pilot collection of PB-DNA for of MAST enrolled patients in limited clinical trials in Table 1. Enrollment of Melanoma Subtypes Per Year ■ A need in Iowa exists for a bank of Melanoma tissue and other Melanoma May 2010. biospecimens. This will provide a potential platform for a Translational bridge with Enrolled Melanoma Subtyes 2008 2009 2010 2011 2012 Total Table 3. Current Status of Patients Enrolled per Year ■ Expanded patient enrollment to UIHC Orthopedic Surgical Clinics in November 2010. Basic Scientists. ■ Initiate collection of PB-DNA for all newly enrolled and metastatic MAST patients in Year Passive MR Tissue Active ■ Provides potential banking of rare Melanoma subtypes such a Ocular, Mucosal Acral Lentginous Melanoma 1 3 1 4 9 March 2011. Enrolled Active CTB WD Only Only WD Total (Vaginal) and Acral Lentiginous melanomas. Amelanotic Melanoma 1 1 1 1 4 ■ Addition of Laboratory Technician to screen, collect, process and enter data for all 2008 12 19 2 1 1 35 blood samples in July 2011. Desmoplastic Melanoma 2 6 1 5 14 OBJECTIVES 2009 53 35 12 5 2 107 Lentigo Maligna Melanoma 4 7 4 2 17 STUDY LIMITATIONS Primary Objective: 2010 76 27 3 2 1 109 Malignant Melanoma, NOS 9 35 24 18 9 95 1) Early stage melanomas not banked 1) Collect and maintain a Repository of Flash frozen samples isolated from fresh skin, 2011 97 17 1 115 2) Most subjects enrolled are at higher risk for relapse at UIHC ocular, lymph node and metastatic tissue tumor specimens from patients with Metastatic Melanoma 8 17 8 7 2 42 3) Data is skewed toward poorer prognoses proliferative disorders of skin and ocular tumors. 2012 33 2 1 36 MM, Malignant Blue Nevus 1 1 2 Tissue Collection: Total 271 100 17 10 1 3 402 a. DNA extraction of tumor tissue and peripheral blood Mucosal Melanoma 1 1 2 1 5 FUTURE GOALS b. RNA extraction of tumor tissue available ■ Involve Dermatology in early stage cancer for more accurate demographic Nodular Melanoma 5 17 23 18 8 71 CTB: cease to breath; WD: withdraw; MR: medical record c. H&E diagnosis confirmation of sample collected representation d. Extra tissue flash frozen and stored for future projects Ocular Melanoma, Chorodial 4 6 5 10 2 27 ■ Optimize banking per specific protocols driven by Basic Scientists 2) Collect and maintain a bank of Serum specimens. Serum samples are collected at Ocular Melanoma, Ciliary Body 1 1 1 3 Table 4. Enrollment & Survival per Gender three time points (before, during and after) each treatment a patient receives. COLLABORATIVE EFFORTS Documented treatment includes chemotherapy, radiation, surgical excisions and Ocular Melanoma, Iris 1 1 2 Gender Alive CTB Total ■ A. Bossler: UIHC clinical review and pathologic examination of BRAF inhibitor in observation. Ocular Melanoma, NOS 1 2 3 melanoma tissue 3) Develop and maintain a clinical registry of subjects with proliferative disorders of Female 147 34 181 ■ DJ Murry: UIHC examination of biomarkers of melanoma subjects. skin and ocular tissue for treatments and outcome. Other 2 2 Male 155 66 221 4) Maintain a secure database to house and track the clinical registry and specimen ■ R Cornell: UIHC examination of biomarkers and validation of extracted RNA from Spindle Cell Melanoma NOS 2 2 repository data. Total 302 100 402 melanoma tissue. Secondary Objective: Superficial Spreading Melanoma 3 14 35 42 10 104 1) Utilize this data for basic and translational research on Melanoma biology, 45% Females enrolled PUBLICATIONS Total 35 107 109 115 36 402 pathophysiology and epidemiology. 55% Males enrolled Meng, X, Milhem, M, Knutson T, Yang S et al. Correlation of MTDH/AEG-1 and HOT 2) Allow for procurement of fresh samples for ongoing collaborative studies that Enrollment began in November 2008 and actively continues in UIHC Oncology and Surgical 34% Females CTB AIR Expression with Metastasis and Response to Treatment in Sarcoma Patients. require tissue from subjects with Proliferative disorders of skin and ocular tissue. Clinics. MM: malignant melanoma; NOS: not otherwise specified. 66% Males CTB Journal of Cancer Science & Therapy. 2011. S5:004.

6 MAST Newsletter Fall/Winter 2014 7 BY THE NUMBERS

Enrollment of Melanoma Subtype Enrolled Per Year Total MAST Subjects Enrolled MAST Enrolled Gender & Per Year and Current Status per Year Mortality Data Melanoma Subtype 2008 2009 2010 2011 2012 2013 2014 Total Year Passive MR Tissue Active Acral Lentginous Melanoma 1 3 1 4 3 12 Enrolled Active CTB WD Only Only WD Total 200 Amelanotic Melanoma 1 1 1 1 1 1 6 2008 12 20 1 1 1 35 CTB Basal Cell Carcinoma, aggress. (non-melanoma) 2 2 2009 43 45 12 6 1 107 150 Alive Desmoplastic Melanoma 2 6 1 5 1 7 1 23 2010 49 39 8 11 1 1 109 Lentigo Maligna Melanoma 1 6 7 4 8 10 1 37 2011 73 33 3 6 115 100 Alive Malignant melanoma, MUP 1 2 3 2 10 1 19 2012 96 29 1 1 1 128 CTB Malignant Melanoma, NOS 4 22 20 14 22 27 1 110 2013 168 13 1 3 185 Malignant melanoma, Spitzoid 1 1 1 3 2014 23 50 23 Metastatic Melanoma 4 12 7 6 6 4 1 40 Total 464 179 25 26 1 7 702 Male Female MM, Malignant Blue Nevus 1 1 2 CTB: Cease to Breathe Active: Follow up done every 6 mo Passive: No active follow up x 3 points 0 Mucosal Melanoma 1 3 1 2 4 2 13 CTB: Cease To Breathe Active: Request to be removed from study WD: Withdraw Tissue: Decline participation in study, 2008 2009 2010 2011 2012 2013 2014 Nodular Melanoma 10 24 26 19 31 35 6 151 MR: Medical Record but provided tissue Ocular Melanoma, Chorodial 4 6 5 10 8 19 4 56

Ocular Melanoma, Ciliary Body 1 1 1 1 4 Enrollment of Sarcoma Subtypes Enrolled Per Year Ocular Melanoma, Iris 1 1 1 1 4 Melanoma Subtype 2008 2009 2010 2011 2012 2013 2014 Total Ocular Melanoma, NOS 1 2 1 4 Angiosarcoma 3 5 4 6 6 7 2 33 Other 2 1 1 4 Carcinosarcoma (prev Mullerian) 1 4 2 5 12 Spindle Cell Melanoma NOS 2 1 3 6 Chondrosarcoma 2 5 5 5 6 2 25 Superficial Spreading Melanoma 5 20 35 42 38 60 6 206 Clear Cell Sarcoma 1 2 1 4 Total 35 107 109 115 128 185 23 702 Dermatofibrosarcoma 2 3 2 1 2 10 Desmoplastic Sm Round Cell Tumor 1 1 1 3 Translational Research Core Endometrial Stromal Sarcoma 1 1 2 4 Epithelioid Sarcoma 1 1 1 3 Ewing's Sarcoma 1 5 4 2 5 6 23 Fibrosarcoma 2 1 1 1 5 Gastrointestinal Stromal Tumor (GIST) 4 13 10 11 10 11 6 65 Giant Cell Sarcoma 1 1 Hemangioendothelioma 1 2 2 5 Kaposi's Sarcoma 1 1 Leiomyosarcoma 11 22 14 22 19 14 2 104 Liposarcoma 7 17 11 7 10 7 6 65 Malignant Fibrous Histiocytoma 2 6 4 2 1 1 16 Myxofibrosarcoma 1 6 4 6 2 11 30 Osteosarcoma 4 6 4 6 2 11 30 Other 2 4 6 Peripheral Nerve Sheath Tumor (PNST) 4 9 4 3 1 3 32 Pleomorphic Sarcoma 1 4 4 1 5 10 1 26 Rhabdomyosarcoma 1 9 1 1 2 14 Sarcoma, NOS 2 3 1 11 3 5 2 27 Solitary Fibrous Tumor 1 2 1 4 Spindle Cell Sarcoma 2 1 2 5 Synovial Sarcoma 2 3 6 5 5 3 24 Total 46 128 86 94 89 105 23 571

8 MAST Newsletter Fall/Winter 2014 9 RESEARCH GROUPS & PARTNERSHIPS 2013 MELANOMA SYMPOSIUM SEED GRANT RECIPIENTS

Dr. Robert Cornell: $25,000 efforts will focus on producing a collection of SB-driven Dr. Michael Schultz: $12,000 Specific Aim: We have identified a clinical NIH R21 mechanism Sarcoma Research Group Midwest Sarcoma Trials Partnership (MSTP) melanoma metastases. These tumors will be analyzed to identify that is specifically targeted to clinical stage proposals as we expect Project: Transgenic delivery of a transcription recurrent mutations associated with a metastatic phenotype. Project: Peptide Receptor Targeted Image- to submit. We have further met with the NIH MD scientist-author factor that promotes melanocyte differentiation Candidate genes will be validated using both mouse models and guided Radionuclide Therapy for Metastatic of the RFA and discussed precisely what preliminary data we need may suppress BRAF-driven melanoma comparative analysis using melanoma metastases collected from Melanomaa for a strong submission. Thus, for submission to the RFA, we must human patients. Our findings could provide biological insight optimize preparation of the 203Pb-labeled radiopharmaceutical and Authors: Robert Cornell, Associate Professor, Authors: Michael K. Schultz PhD and Department of Anatomy and Cell Biology into the mechanisms that drive melanoma metastasis and could Yusuf Menda MD, Radiology; Co-Investigator provide three successive preparations that meet release criteria for be used to develop therapies that specifically target these Thomas Quinn PhD, University of Missouri, submission of an Investigational New Drug application. This activity Purpose: Melanoma tumors are derived from cells in the processes. Department of Biochemistry. is the primary focus of the research team for this research. melanocyte lineage. However, expression profile data at the NIH Cancer Genome Atlas reveals that melanoma tumors resemble Primary melanoma tumors identified early can be Potential Impact: Upon successful completion of our overall Background: 203 Miller Milhem neural crest, the precursor population from which melanocytes Dr. Frederick Domann: $12,000 cured by surgery, but metastatic melanoma is lethal (10 yr survival research, we expect to have demonstrated the potential of Pb- ReCCMSH for imaging metastatic melanoma patients. We further Benjamin Miller, MD, MS, are derived, more than they do melanocytes themselves. In < 10%). Currently, no systemic therapy provides durable benefit Leader: Project: CpG methylation of PHD3 is a novel expect to have developed a detailed understanding of the key Assistant Professor, Department of particular, the expression of genes that promote melanocyte to metastatic melanoma patients. In fact, the standard of care for biomarker for melanoma progression components and conditions for 212Pb-ReCCMSH dose Orthopaedics & Rehabilitation differentiation, and suppress pluripotency, cell growth, and metastatic melanoma has not changed since FDA approval of the migration of neural crest, is much lower in melanoma than in alkylating agent dacarbazine in 1975, although interleukin-2 preparation/ formulation that lead to optimal stability and tumor Authors: Trenton L. Place, Sabine U. Vorrink, Co-Leader: Mo Milhem, MD, Deputy melanocytes. We previously found that the transcription factor therapy (FDA approved, 1998) shows modest improvement for a targeting for treating melanoma patients. With these advances, we Frederick E. Domann, PhD. 203 Director of Clinical Cancer Services at Activator Protein 2 alpha (TFAP2A) promotes differentiation of few patients. Recently approved FDA treatments appear promis- anticipate identifying and optimizing a Pb dosimetry approach 212 the Holden Comprehensive Cancer neural crest into melanocytes in zebrarish. Here we have tested ing, but durable benefit remains elusive. Targeted radionuclide that prepares us to proceed to Pb therapy. The research proposed Center, Professor, Department of the therapeutic potential of forcing expression of TFAP2A within Proline hydroxylation of the hypoxia inducible factor therapy has long been considered a promising therapeutic here is innovative because it would lead to the first in humans clinical Summary: 203 Internal Medicine, Division of Hematol- MSTP Chicago 2013 zebrafish BRAF-driven metastatic melanoma. We injected HIF-1a is an important mode of hypoxia stimulated alternative for cancer treatment, but translation of discovery to trial with a Pb radiolabeled Re-MSH peptide (DOTA-ReCCMSH) ogy, Oncology and Blood & Marrow melanoma prone zebrafish embryos with a plasmid vector that post-translational signal transduction. The hydroxylation reaction clinically relevant therapies has proven challenging. On the other that targets the melanocotrin 1 receptor (MC1R) for melanoma Transplantation drives expression of TFAP2A specifically in cells of the melanocyte is accomplished by the oxygen dependent HIF-1a prolyl-4- hand, recent successes in our laboratories and clinics not only provide imaging and supports the advancement of an innovative MC1R ■ Mission: To improve the care of patients Collaborating partners include: 212 lineage. In preliminary studies, two animals injected with control hydroxylase family of enzymes PHD1-3. Although all three of preclinical evidence that targeted radionuclide therapy can targeted melanoma alpha+beta particle therapy with Pb. The Sarcoma MOG (Multidisciplinary living with sarcomas ■ Mayo Clinic vectors developed large tumors by 12 weeks post fertilization these proteins can target HIF-1a for degradation, only PHD3 is circumvent resistance pathways to provide effective treatment for Oncology Group) meets monthly with ■ To be the premier Midwest Vision: ■ University of Iowa (dpf) and died by 16 weeks dpf, while an animal injected with the inducible by hypoxia. Moreover, PHD3 silencing is associated metastatic melanoma, but also that peptide-receptor targeted presentations by many different facets of collaboration of institutions for sarcomas ■ Northwestern University TFAP2A vector is alive and tumor free at 24 dpf. A replicate of with an epithelial to mesenchymal transition in several cell types. radionuclide therapy can be safely and effectively administered to Dr. Anthony Snow: $15,500 the cancer center. This collaboration ■ MSTP consists of 8 medical oncologists the experiment with larger numbers of individuals is underway. If We previously showed that PHD3 silencing in a human melanoma provide benefit to cancer patients. Further, our team from the fosters ingenuity and translational ■ Washington University- St, Louis BRAF and NRAS Mutations in Nodular who specialize in the treatment of the trend in the results continues, further investigations of the cell line was associated with an aberrantly methylated PHD3 gene, University of Missouri (MU) and University of Iowa (UI) has Project: ■ University of Wisconsin and Superficial Spreading Melanoma concepts in sarcoma as well as seed sarcoma from 6 institutions in the therapeutic potential of elevating TFAP2A in melanoma tumors, and that PHD3 could be induced by 5-aza-deoxycytidine, a DNA identified an innovative peptide-based ligand that not only binds funding to promising ideas. Midwest. Together they work on creating ■ University of Minnesota and the mechanism by which doing so suppresses tumor forma- methyltransferase inhibitor. Additionally, our previous bioinfor- with high affinity to a cell surface receptor that is upregulated in Authors: Anthony Snow, MD, Natasha Guseva, The Sarcoma Research Group had its new clinical trials. tion, are warranted. An important objective is to identify methods matic searches of existing human melanoma data in the Onco- metastatic melanoma, but is also virtually undetectable in most Nick Wilson, Tina Knutson, Anna Button, MS, first annual sarcoma symposium on to elevate TFAP2A expression in melanoma; DNA methyl transfer- mine and TCGA databases revealed that PHD3 expression other human tissue and organs. The molecular therapy design Mohammed M. Milhem, MD, Aaron D. Bossler, March 8, 2013. Forty-two University of Melanoma Research Group ase inhibitors may have this potential. progressively deceased during melanoma progression and this was combines improved tumor targeting with novel alpha+beta PhD. radiation to maximize dose to tumors, while minimizing dose to Iowa staff and faculty attended and heard Leader: Mo Milhem, MD, Professor, Department of Internal Medicine, Division of occasionally accompanied by CpG methylation in a region near presentations from 17 researchers. Five Hematology, Oncology and Blood & Marrow Transplantation the 5’ end of the PHD3 gene. The lowest expression levels of healthy tissues and organs. These exciting developments and Departments of Pathology, Internal Medicine; and Epidemiology projects and seven researchers were Dr. Adam Dupuy: $16,000 PHD3 were consistently found in distant organ metastases in knowledge define a new paradigm for metastatic melanoma and Biostatistics, University of Iowa, Carver College of Medicine, Iowa City, IA. Department of Pathology, Brown University, Provi- given grants totalling $88,471.00 to The Melanoma MOG meets monthly to share and discuss melanoma-related projects contrast to primary tumors and lymph node metastases however therapy based on peptide receptor targeted alpha-beta particle A forward genetic approach dence, RI support their sarcoma-related projects. that are being worked on at the University of Iowa. The 2nd annual Melanoma Project: role of DNA methylation in this phenomenon is unknown. therapy that has yet to be explored clinically. The investigators to identify mechanisms of melanoma Therefore, we aimed to determine whether aberrant cytosine have not only demonstrated the potential for this new patented Symposium was held on February 8, 2013 and was attended by 74 staff and faculty. Virtually all types of cancer are known to have multiple ■ Jessica Geotz, PhD metastasis methylation of the PHD3 gene contributed to the loss of its form of treatment preclinically, but also have completed the Summary: Twenty-nine researchers shared their melanoma-related projects with the group. genetic defects that divert cells from a path toward development of Awarded: $10,500.00 expression in melanoma metastases. We obtained 11 human required FDA-directed toxicity studies and have GMP- Kaitlyn Zenner, Marisa Buchakjian, normal tissue within the body toward one of uncontrolled growth Project: The Effects of Radiation Dosing Authors: metastatic melanoma samples from the Melanoma And Sarcoma pharmaceutical grade material required for human studies in MD, PhD, Michael Henry, PhD, Adam J. Dupuy and tumor formation. Melanoma is no exception to this rule. Regimen on Mechanical Strength of Bone Midwest Melanoma Partnership (MMP) Tissue (MAST) bank. Of these, 8 were lymph node metastases and hand. There is therefore, a critical need to refine molecular ■ However, the changes in the DNA in melanoma are many and Lyse Norian, PhD Metastasis is largely responsible for melanoma 3 were organ metastases. DNA was extracted by the MAST and targeting for radionuclide therapy of metastatic melanoma to take Awarded: $20,000 Summary: varied. Our group reviewed current literature and clinical testing associated morbidity and mortality. Fortunately the establishment total RNA was isolated by the Tissue Procurement Core. From advantage of these developments and preliminary evidence Project: Elucidating Obesity-Dependent options to identify gene targets that have the potential to demon- of metastatic melanoma is an inefficient process — only rare these nucleic acids we measured PHD3 mRNA expression levels Mechanisms of Immune Suppression in strate DNA changes that can be useful for prognostic information disseminated melanoma cells produce metastatic lesions. Unfor- by qRT-PCR and gene methylation profiles by bisulfite sequencing Objectives: Our overall objectives in this research are: (i) to Sarcoma 203 or for selection of therapeutic options. Typically, these changes are tunately, little is known about the biological mechanisms that in each of the samples. PHD3 expression was variable and develop a rhenium-cyclized lead-203 ( Pb-) labeled peptide, ■ identified using methods that copy, or amplify, the DNA in a Mitch Coleman, PhD determine which melanoma cells will produce metastases. We generally down-regulated across all specimens. PHD3 gene targeted to the melanocortin subtype 1 receptor (MC1R), for Awarded: $19,435.00 sequence-specific manner. This is commonly done using variations have developed a mouse model of melanoma in which Sleeping methylation was rare among these samples, with 0/8 lymph node SPECT imaging of metastatic melanoma in human patients; and Project: Radiosensitization of Leiomyosar- of the polymerase chain reaction (PCR) or traditional Sanger Beauty (SB) transposon mutagenesis is used to drive metastasis in metastases displaying PHD3 methylation. Notably however, 1/3 of (ii) to develop a detailed understanding of the radiopharmaceuti- coma and Liposarcoma via Metabolic sequencing. Thanks to the generosity of the patients and families vivo. The SB system is a powerful tool that has been used for the organ metastases had an aberrantly methylated PHD3 cal formulation (e.g., specific activity, radiolysis protection, etc.) Oxidative Stress Induced by Inhibition of 212 who have donated research funds, we have developed a panel of cancer gene discovery in a variety of tumor types in mice. We promoter. We attempted to follow-up on this observation and that lead to a highly stable, high specific activity Pb labeled Glucose Metabolism 212 potentially clinically useful targets that can be examined at the have engineered the SB system components into B16-F0 hopefully achieve statistical significance by obtaining additional peptide for alpha+beta-particle therapy using Pb-labeled ■ Jiwoong Choi, PhD same time from one sample. The technology is called next genera- melanoma cells, a spontaneous mouse melanoma cell line with organ met samples from the MAST but were unsuccessful due to peptide. Our central hypothesis is that image-guided radionuclide Awarded: $20,000 203 212 tion sequencing and uses equipment called the Ion Torrent very low metastatic potential. We hypothesize that the SB system limited sample availability. Nevertheless as additional clinical therapy (using Pb for imaging and Pb for alpha+beta particle Project: QCT Image Matching Assessment treatment) can be developed for effective treatment for metastatic Personal Genome Machine. The test includes a total of 25 gene of Lung Biomechanical Signals of Cancer will drive metastasis by generating genetic variants of B16-F0 that samples become available, particularly from patients before and melanoma. This hypothesis was formulated, in part, based on our targets. Many of the targets are known to be involved in the Patients are capable of metastasizing to distant sites within the host animal. after treatment with 5-aza-deoxycytidine. In conclusion, PHD3 is Pat Gavin and Cynthia Chauhan preliminary data, which demonstrated that our 212Pb-labeled formation of melanoma, while others are included in hopes of ■ To test our hypothesis, engineered B16-F0 cells were subcutane- an epigenetically labile target silenced by DNA methylation in Darrion Mitchell, MD, PhD, gaining new information about the role they may play in clinical ously injected into the interscapular region of female C57B/6N distant organ metastases; thus, acquisition of PHD3 expression Re-cyclized peptide (ReCCMSH) cured mice bearing melanoma Marisa Buchakjian, MD, PhD, outcome and treatment options. We have already identified ■ to facilitate the sharing of ideas, clinical trials and resources in an effort mice. Two weeks after injection the primary tumors were excised, following decitabine therapy could be a valuable biomarker for tumors. Further preliminary evidence demonstrated that peptide Michael Henry, PhD Mission: mutations that were not known to be in the samples that were Awarded: $18,536.00 to improve the diagnosis, treatment and long-term care of melanoma patients. and the mice were periodically monitored for metastases to the drug action in vivo. targeted radionuclide therapy is well-tolerated in human patients examined. The next step is comparing the clinical information to Project: Developing a Model to Test ■ MMP consists of health care professionals including medical oncologists from 18 lungs, brain, and reproductive tract. Preliminary data suggests in our clinics. The rationale for our research is that success in our the test results to identify ways to use the information to improve Autophagy as a Therapeutic Target in institutions across the United States as well as patient advocates. that SB mutagenesis will produce metastatic lesions at a rate much aims will lead to reliable therapy for metastatic melanoma by patient care. Soft-Tissue Sarcomas ■ www.midwestmelanoma.org higher than is observed using negative control cells. Our future directing alpha+beta radiation dose precisely to tumor tissue.

10 MAST Newsletter Fall/Winter 2014 11

2013 MELANOMA SYMPOSIUM SEED GRANT RECIPIENTS PHOTOS

Dr. Robert Cornell: $25,000 efforts will focus on producing a collection of SB-driven Dr. Michael Schultz: $12,000 Specific Aim: We have identified a clinical NIH R21 mechanism 2013 Courage Ride, an annual bike 2013 Miles 2 Give, a team of extreme athletes who run across the country melanoma metastases. These tumors will be analyzed to identify that is specifically targeted to clinical stage proposals as we expect ride honoring the courageous life to raise money for sarcoma Peptide Receptor Targeted Image- Project: Transgenic delivery of a transcription recurrent mutations associated with a metastatic phenotype. Project: to submit. We have further met with the NIH MD scientist-author of Seth Bailey (synovial sarcoma) http://www.miles2give.org guided Radionuclide Therapy for Metastatic factor that promotes melanocyte differentiation Candidate genes will be validated using both mouse models and of the RFA and discussed precisely what preliminary data we need http://www.courageride.org may suppress BRAF-driven melanoma comparative analysis using melanoma metastases collected from Melanomaa for a strong submission. Thus, for submission to the RFA, we must human patients. Our findings could provide biological insight optimize preparation of the 203Pb-labeled radiopharmaceutical and Authors: Robert Cornell, Associate Professor, Authors: Michael K. Schultz PhD and Department of Anatomy and Cell Biology into the mechanisms that drive melanoma metastasis and could Yusuf Menda MD, Radiology; Co-Investigator provide three successive preparations that meet release criteria for be used to develop therapies that specifically target these Thomas Quinn PhD, University of Missouri, submission of an Investigational New Drug application. This activity Purpose: Melanoma tumors are derived from cells in the processes. Department of Biochemistry. is the primary focus of the research team for this research. melanocyte lineage. However, expression profile data at the NIH Cancer Genome Atlas reveals that melanoma tumors resemble Primary melanoma tumors identified early can be Potential Impact: Upon successful completion of our overall Background: 203 neural crest, the precursor population from which melanocytes Dr. Frederick Domann: $12,000 cured by surgery, but metastatic melanoma is lethal (10 yr survival research, we expect to have demonstrated the potential of Pb- are derived, more than they do melanocytes themselves. In < 10%). Currently, no systemic therapy provides durable benefit ReCCMSH for imaging metastatic melanoma patients. We further particular, the expression of genes that promote melanocyte Project: CpG methylation of PHD3 is a novel to metastatic melanoma patients. In fact, the standard of care for expect to have developed a detailed understanding of the key 212 differentiation, and suppress pluripotency, cell growth, and biomarker for melanoma progression metastatic melanoma has not changed since FDA approval of the components and conditions for Pb-ReCCMSH dose migration of neural crest, is much lower in melanoma than in alkylating agent dacarbazine in 1975, although interleukin-2 preparation/ formulation that lead to optimal stability and tumor Authors: Trenton L. Place, Sabine U. Vorrink, melanocytes. We previously found that the transcription factor therapy (FDA approved, 1998) shows modest improvement for a targeting for treating melanoma patients. With these advances, we Frederick E. Domann, PhD. 203 Activator Protein 2 alpha (TFAP2A) promotes differentiation of few patients. Recently approved FDA treatments appear promis- anticipate identifying and optimizing a Pb dosimetry approach 212 neural crest into melanocytes in zebrarish. Here we have tested ing, but durable benefit remains elusive. Targeted radionuclide that prepares us to proceed to Pb therapy. The research proposed the therapeutic potential of forcing expression of TFAP2A within Proline hydroxylation of the hypoxia inducible factor therapy has long been considered a promising therapeutic here is innovative because it would lead to the first in humans clinical Summary: 203 zebrafish BRAF-driven metastatic melanoma. We injected HIF-1a is an important mode of hypoxia stimulated alternative for cancer treatment, but translation of discovery to trial with a Pb radiolabeled Re-MSH peptide (DOTA-ReCCMSH) melanoma prone zebrafish embryos with a plasmid vector that post-translational signal transduction. The hydroxylation reaction clinically relevant therapies has proven challenging. On the other that targets the melanocotrin 1 receptor (MC1R) for melanoma drives expression of TFAP2A specifically in cells of the melanocyte is accomplished by the oxygen dependent HIF-1a prolyl-4- hand, recent successes in our laboratories and clinics not only provide imaging and supports the advancement of an innovative MC1R 212 lineage. In preliminary studies, two animals injected with control hydroxylase family of enzymes PHD1-3. Although all three of preclinical evidence that targeted radionuclide therapy can targeted melanoma alpha+beta particle therapy with Pb. vectors developed large tumors by 12 weeks post fertilization these proteins can target HIF-1a for degradation, only PHD3 is circumvent resistance pathways to provide effective treatment for (dpf) and died by 16 weeks dpf, while an animal injected with the inducible by hypoxia. Moreover, PHD3 silencing is associated metastatic melanoma, but also that peptide-receptor targeted TFAP2A vector is alive and tumor free at 24 dpf. A replicate of with an epithelial to mesenchymal transition in several cell types. radionuclide therapy can be safely and effectively administered to Dr. Anthony Snow: $15,500 the experiment with larger numbers of individuals is underway. If We previously showed that PHD3 silencing in a human melanoma provide benefit to cancer patients. Further, our team from the BRAF and NRAS Mutations in Nodular the trend in the results continues, further investigations of the cell line was associated with an aberrantly methylated PHD3 gene, University of Missouri (MU) and University of Iowa (UI) has Project: and Superficial Spreading Melanoma therapeutic potential of elevating TFAP2A in melanoma tumors, and that PHD3 could be induced by 5-aza-deoxycytidine, a DNA identified an innovative peptide-based ligand that not only binds and the mechanism by which doing so suppresses tumor forma- methyltransferase inhibitor. Additionally, our previous bioinfor- with high affinity to a cell surface receptor that is upregulated in Authors: Anthony Snow, MD, Natasha Guseva, tion, are warranted. An important objective is to identify methods matic searches of existing human melanoma data in the Onco- metastatic melanoma, but is also virtually undetectable in most Nick Wilson, Tina Knutson, Anna Button, MS, to elevate TFAP2A expression in melanoma; DNA methyl transfer- mine and TCGA databases revealed that PHD3 expression other human tissue and organs. The molecular therapy design Mohammed M. Milhem, MD, Aaron D. Bossler, ase inhibitors may have this potential. progressively deceased during melanoma progression and this was combines improved tumor targeting with novel alpha+beta PhD. occasionally accompanied by CpG methylation in a region near radiation to maximize dose to tumors, while minimizing dose to the 5’ end of the PHD3 gene. The lowest expression levels of healthy tissues and organs. These exciting developments and Departments of Pathology, Internal Medicine; and Epidemiology Dr. Adam Dupuy: $16,000 PHD3 were consistently found in distant organ metastases in knowledge define a new paradigm for metastatic melanoma and Biostatistics, University of Iowa, Carver College of Medicine, contrast to primary tumors and lymph node metastases however therapy based on peptide receptor targeted alpha-beta particle Iowa City, IA. Department of Pathology, Brown University, Provi- Project: A forward genetic approach role of DNA methylation in this phenomenon is unknown. therapy that has yet to be explored clinically. The investigators dence, RI to identify mechanisms of melanoma Therefore, we aimed to determine whether aberrant cytosine have not only demonstrated the potential for this new patented Virtually all types of cancer are known to have multiple metastasis methylation of the PHD3 gene contributed to the loss of its form of treatment preclinically, but also have completed the Summary: genetic defects that divert cells from a path toward development of expression in melanoma metastases. We obtained 11 human required FDA-directed toxicity studies and have GMP- Kaitlyn Zenner, Marisa Buchakjian, normal tissue within the body toward one of uncontrolled growth Authors: metastatic melanoma samples from the Melanoma And Sarcoma pharmaceutical grade material required for human studies in MD, PhD, Michael Henry, PhD, Adam J. Dupuy and tumor formation. Melanoma is no exception to this rule. Tissue (MAST) bank. Of these, 8 were lymph node metastases and hand. There is therefore, a critical need to refine molecular However, the changes in the DNA in melanoma are many and Metastasis is largely responsible for melanoma 3 were organ metastases. DNA was extracted by the MAST and targeting for radionuclide therapy of metastatic melanoma to take Summary: varied. Our group reviewed current literature and clinical testing associated morbidity and mortality. Fortunately the establishment total RNA was isolated by the Tissue Procurement Core. From advantage of these developments and preliminary evidence options to identify gene targets that have the potential to demon- of metastatic melanoma is an inefficient process — only rare these nucleic acids we measured PHD3 mRNA expression levels strate DNA changes that can be useful for prognostic information disseminated melanoma cells produce metastatic lesions. Unfor- by qRT-PCR and gene methylation profiles by bisulfite sequencing Objectives: Our overall objectives in this research are: (i) to 203 or for selection of therapeutic options. Typically, these changes are tunately, little is known about the biological mechanisms that in each of the samples. PHD3 expression was variable and develop a rhenium-cyclized lead-203 ( Pb-) labeled peptide, identified using methods that copy, or amplify, the DNA in a determine which melanoma cells will produce metastases. We generally down-regulated across all specimens. PHD3 gene targeted to the melanocortin subtype 1 receptor (MC1R), for sequence-specific manner. This is commonly done using variations have developed a mouse model of melanoma in which Sleeping methylation was rare among these samples, with 0/8 lymph node SPECT imaging of metastatic melanoma in human patients; and of the polymerase chain reaction (PCR) or traditional Sanger Beauty (SB) transposon mutagenesis is used to drive metastasis in metastases displaying PHD3 methylation. Notably however, 1/3 of (ii) to develop a detailed understanding of the radiopharmaceuti- sequencing. Thanks to the generosity of the patients and families vivo. The SB system is a powerful tool that has been used for the organ metastases had an aberrantly methylated PHD3 cal formulation (e.g., specific activity, radiolysis protection, etc.) 212 who have donated research funds, we have developed a panel of cancer gene discovery in a variety of tumor types in mice. We promoter. We attempted to follow-up on this observation and that lead to a highly stable, high specific activity Pb labeled 212 potentially clinically useful targets that can be examined at the have engineered the SB system components into B16-F0 hopefully achieve statistical significance by obtaining additional peptide for alpha+beta-particle therapy using Pb-labeled same time from one sample. The technology is called next genera- melanoma cells, a spontaneous mouse melanoma cell line with organ met samples from the MAST but were unsuccessful due to peptide. Our central hypothesis is that image-guided radionuclide 203 212 tion sequencing and uses equipment called the Ion Torrent very low metastatic potential. We hypothesize that the SB system limited sample availability. Nevertheless as additional clinical therapy (using Pb for imaging and Pb for alpha+beta particle Personal Genome Machine. The test includes a total of 25 gene will drive metastasis by generating genetic variants of B16-F0 that samples become available, particularly from patients before and treatment) can be developed for effective treatment for metastatic targets. Many of the targets are known to be involved in the are capable of metastasizing to distant sites within the host animal. after treatment with 5-aza-deoxycytidine. In conclusion, PHD3 is melanoma. This hypothesis was formulated, in part, based on our 212 formation of melanoma, while others are included in hopes of To test our hypothesis, engineered B16-F0 cells were subcutane- an epigenetically labile target silenced by DNA methylation in preliminary data, which demonstrated that our Pb-labeled gaining new information about the role they may play in clinical ously injected into the interscapular region of female C57B/6N distant organ metastases; thus, acquisition of PHD3 expression Re-cyclized peptide (ReCCMSH) cured mice bearing melanoma outcome and treatment options. We have already identified mice. Two weeks after injection the primary tumors were excised, following decitabine therapy could be a valuable biomarker for tumors. Further preliminary evidence demonstrated that peptide mutations that were not known to be in the samples that were and the mice were periodically monitored for metastases to the drug action in vivo. targeted radionuclide therapy is well-tolerated in human patients examined. The next step is comparing the clinical information to lungs, brain, and reproductive tract. Preliminary data suggests in our clinics. The rationale for our research is that success in our the test results to identify ways to use the information to improve that SB mutagenesis will produce metastatic lesions at a rate much aims will lead to reliable therapy for metastatic melanoma by patient care. higher than is observed using negative control cells. Our future directing alpha+beta radiation dose precisely to tumor tissue.

12 MAST Newsletter Fall/Winter 2014 13 PHOTOSPHOTOS

2014 Tips for Tad, annual fundraiser 2014 Melanoma Monday, HCCC staff wearing black to raise melanoma 2013-14 Steve Yates Melanoma Awareness Golf Tournament , annual 2013-14 Drive Out Sarcoma, annual in honor of Tad Agnew (melanoma) awareness fundriaser in Waterloo, Iowa in honor of Steve Yates golf tournament in Kewanee, http://www.steveyatesmelanomaawareness.org Illinois, in honor of Jim Burkhart (synovial sarcoma)

Jim Burkhart and Gang.

Marty Bunge and Jan Stewart

Flyer for Tips for Tad

2013 Ride It Out for Amber, annual motorcycle ride in Polk City, Iowa, 2013 in honor of Amber Birmingham (osteosarcoma)

University of Iowa Melanoma Epigenetics Working Group

2014 Herky on Parade, “My Hero Herky” was designed to honor Abbey Almelien Banh (malignant peripheral nerve sheath tumor, sarcoma)

Mo with Paula Sands from the Paula Sands Live show L to R: Dr. Frederick Domann, Dr. Aaron Bossler, Dr. Michael Henry, Jimmy Schappet, Mo, Dr. Robert Cornell, Dr. Roberto (promoting Tips for Tad) Leon-Ferre

14 MAST Newsletter Fall/Winter 2014 15