Originally published in Health Canal

Mitochondrial function steps in to save cancer cells after tumor-driving mutation is stifled.

Knock out a genetic mutation that’s a driving force behind pancreatic cancer and a few cells quietly hunker down in the resulting scar tissue, nibbling on themselves to survive before roaring back as resistant disease that taps the cell’s normal powerhouses to thrive.  

Scientists at The University of Texas MD Anderson Cancer Center reveal this mode of metabolic resistance to targeted cancer therapy and a way to attack it in a paper published online in Nature.
Their findings raise the possibility of combining a drug that inhibits the function of mitochondria, the cell’s main energy producers, with targeted therapies to thwart pancreatic cancer recurrence.

“Effective therapies that target specific genes can have an incredible initial impact. Cancerous lesions disappear, but they all come back, all of them,” said senior author Giulio Draetta, Ph.D., M.D.,  professor of Molecular and Cellular Biology.  “So there must be something left behind. We’re interested in what’s left behind.”

“Targeting mitochondrial function with drugs called OXPHOS inhibitors to overcome resistance to targeted therapies would be an entirely new paradigm in cancer treatment,” said Draetta, also a professor of Genomic Medicine.

Surviving without KRAS
Draetta said Andrea Viale, Ph.D., instructor in Genomic Medicine and lead author of the paper, wanted to know whether tumor-initiating pancreatic cancer stem cells need an active oncogene to survive.
The scientists’ research focused on KRAS, a gene whose mutated versions are known to drive development and progression of pancreatic ductal adenocarcinoma, largely incurable cancer with only a 6 percent survival rate at five years.

They developed a unique mouse model that allows them to induce KRAS-driven pancreatic cancer and then turn KRAS off. The mice are genetically engineered so that treating them with the antibiotic doxycycline activates KRAS expression in the pancreas.  When the researchers withdrew doxycycline, tumors regressed in two or three weeks, but then returned in 4-5 months with KRAS still turned off.

Nests of surviving cells were found in fibrotic scar tissue left after KRAS-deprived tumors appeared to completely regress.

“The surviving cells were dormant, and there was lots of autophagy – essentially they were eating pieces of themselves,” Draetta said. The survivors had many characteristics of pancreatic cancer stem cells.

Metabolic differences, not genetic mutations, drive resistance
Additional analysis showed that the resistant cells did not arise via genetic selection of new dominant mutations after KRAS was gone.  

Instead, there was strong expression of genes that govern mitochondrial function and mitochondrial respiration.  Cellular mitochondria are the main metabolic power plants of the cell, using oxygen to convert fatty acids and proteins into energy by a process of oxidative phosphorylation (OXPHOS).

The resistant cells also relied less on another method of energy production called glycolysis, the conversion of glucose to energy in the absence of oxygen, which is commonly found in cancer.
“We suspected that this reliance on mitochondrial respiration made these resistant tumors vulnerable to OXPHOS inhibitors,” Draetta said.

OXPHOS and KRAS inhibition work together
The team found that treating resistant cells and KRAS-dependent cells with the OXPHOS inhibitor oligomycin reduced mitochondrial respiration in both cell types.  While KRAS-dependent cells made up for the energy loss by increasing glycolysis, the survivor cells could not compensate for the resulting energy deficit.

Subsequent experiments showed that oligomycin treatment reduced the ability of cells to form tumor spheres and increased the survival of mice.

KRAS so far cannot be directly targeted by a drug but two pathways that it regulates, MEK and PI3K, can.  Draetta said the collaborators are studying combinations of MEK, PI3K and OXPHOS inhibitors as well as moving OXPHOS drugs toward the clinic. MD Anderson’s Institute of Applied Cancer Science is developing an OXPHOS inhibitor.

Draetta and collaborator Lewis Cantley, Ph.D., Joan and Sanford I. Weill Medical College of Cornell University, New York, were awarded a three-year, $1 million grant earlier this year by the Pancreatic Cancer Action Network and the American Association for Cancer Research titled “Developing a novel oxidative phosphorylation inhibitor in pancreatic cancer.”

“This approach will need to be managed carefully because mitochondrial function is required for many vital functions,” Draetta said.  So far preclinical studies indicate this can be done safely, but the next step is to undertake formal toxicology studies.  “We need to be cautiously optimistic at this point.”

“We’re excited that we aren’t just targeting the proliferating cells in a tumor,” Draetta said. “A large portion of a tumor doesn’t proliferate, it’s just sitting there dormant, making a mess, and secreting harmful cytokines that affect patients’ performance status.”

Co-authors with Viale and Draetta are co-lead author Piergiorgio Pettazzoni, Haoqiang Ying, Nora Sanchez, Matteo Marchesini, Alessandro Carugo, Tessa Green, Florian Muller, Simona Colla, Luigi Nez, Giannicola Genovese, Angela K. Deem, Avnish Kapoor, Wantong Yao and Y. Alan Wang of Medical Genomics;  Costas Lyssiotis and Cantley of Weill Cornell Medical College, New York; Sahil Seth, Virginia Giuliani, Maria Kost-Alimova, and Timothy Heffernan of MD Anderson’s Institute for Applied Cancer Science;  Emanuela Brunetto of San Raffaele Scientific Institute, Milan, Italy; Ya’an Kang and Jason Fleming of Surgical Oncology at MD Anderson; Min Yuan,  and John M. Asara of Beth Israel Deaconness Hospital, Boston;  Alec Kimmelman of Dana-Farber Cancer Institute, Boston; Huamin Wang MD Anderson Pathology; and Ronald DePinho, MD Anderson Cancer Biology.

This research was funded by the Hirshberg Foundation for Pancreatic Cancer Research, the Harvard Stem Cell Institute, Sheikh Ahmed Center for Pancreatic Cancer Research at MD Anderson, American Italian Cancer Foundation, The National Cancer Institute of the National Institutes of Health (P01CA117969, NCI P01CA120964), The Viragh Family Foundation,  a Pancreatic Cancer Action Network-AACR Pathway to Leadership Fellowship and MD Anderson’s NCI Cancer Center Support Grant (CA16672).

By Sarah Banks

In 2012, we featured a story about Brad Dal Bon and the annual golf tournament his family hosts in memory of both his parents. We are happy to share that just two years later, the Dal Bon Memorial Golf Tournament has raised nearly $30,000! The event has become a tradition and a way for their family to “catch up on a yearly basis.” Brad and his wife Amy organize the golf tournament for 75 golfers, plan activities for the day of and collect raffle prizes from community sponsors all in midst of their busy lives with two sons. Their commitment is being passed on, “Having our sons see how passionate we are about this helps them want to get involved in the future,” writes Brad. And it isn’t just the Dal Bon family that has been inspired. “The community involvement with sponsors, golfers and friends has been amazing.” In regards to next year, Brad states, “Obviously, the cause is very important… We are just looking forward to year 7! “

In our 2012-2013 Seed Grant Program Alexander Tzatsos, MD, PhD, was a recipient of a $50,000 award to study the epigenetics of pancreatic cancer. We are pleased to announce he has just received more than $1 million in funding from National Institute of Health (NIH). This recognition of Dr. Tzastos’s work is another positive outcome for our investment towards the cure!

Dr. Tzastos shared his appreciation with us. “We are really happy and fortunate that we secured significant funding to study pancreatic cancer for the next 3-4 years. In fact, this is largely due to the seed grant from the Hirshberg Foundation that allowed us to take the risk and generate all the necessary preliminary data to submit those successful applications.”

Read the full announcement →

The Hirshberg Seed Grant Program began in 2000 to provide start-up funds for scientists with innovative ideas for improving diagnosis, developing new treatment modalities and to impact the understanding of pancreatic cancer cell biology. To date, we estimate $45 million in government funding received from our selected awardees. We thank our distinctive Scientific Advisory board for their outstanding collaboration.

Our next grant cycle begins on August 15, 2014 and we expect more qualified applicants than ever before. We need your continued support to take us another step closer to a pancreatic cancer-free life!

By Elissa Oblath

Among the many amazing events hosted by our passionate supporters to benefit our foundation during 2014, the June 8^th Cooking for a Cure stands out as the tastiest. Plan Check Bar + Kitchen graciously offered a wonderful setting and Executive Chef Ernesto Uchimira welcomed a dazzling array of fellow chefs to serve up delicious bites. Joining chef Ernesto were “Top Chef” champ Michael Voltaggio, chef Josef Centeno of Bäco Mercat & Bar Ama fame, award-winning BierBeisl Chef/Owner Bernhard Mairinger, Waterloo & City chef and a food TV rising star Brendan Collins and James Beard-nominated culinary masters Jon Shook and Vinny Dotolo.

Held to benefit pancreatic cancer research, with an emphasis on the emotional support provided by the Hirshberg Foundation’s relationship to the Simms-Mann Center at UCLA, the event raised over $17,000. The event board, a passionate group of friends including Jeff Price, Terry Heller, Joey Leff, Jessica Sorgini and Gay Harwin, came together to support a friend currently in treatment.

From Voltaggio’s delicate asparagus with horseradish powder and caviar to Shook & Dotolo’s crispy-skinned and juicy smoked chicken leg to Uchimura’s creamy cheesy grits topped with the perfect egg and fresh green peas, there was something for everyone. Centeno brought a burrito twist on his signature bäco with pork asada and beef albondigas with a creamy tomato sauce and just the right heat. Collins’ veal tongue with uni on a dark toast topped with apricots and a porcini was a crowd favorite for its play on textures and strong flavors. Mairinger’s sous chef came prepared with his purple apron to serve up seared duck breast appropriately paired with a purple cabbage salad. With the windows open and a summer breeze, the intimate afternoon allowed participants to mingle with chefs and friends while supporting pancreatic cancer. A Tito’s Vodka, watermelon and mint passed punch was available as well as specialty jalapeno-infused cocktail by Livigni + Moix and Matthew Biancaniello’s famous Breeder’s Cup. To say the afternoon was a culinary adventure is to say the least! But to think that it all benefited pancreatic cancer patients was the most delicious part of it all.

Pancreatic cancer prevention is a very important part of our research funding programs. We are pleased to recognize Dr. Wai-Nang Lee, on his recent publication that identifies the mechanism of action of phytochemicals that reduce the risk of pancreatic cancer. He and his team received a Hirshberg Foundation Seed Grant in 2013. Last week the study, “Metabolic consequences of LDHA inhibition by epigallocatechin gallate and oxamate in MIA PaCa-2 pancreatic cancer cells” was published and we wanted to share this exciting news with all of you. In a recent interview Dr. Lee said, “By explaining how green tea’s active component could prevent cancer, this study will open the door to a whole new area of cancer research and help us understand how other foods can prevent cancer or slow the growth of cancerous cells.” Congratulations to Dr. Lee and his research team for their promising findings.

Read Full Article →

Read Statement →

At the Hirshberg Foundation, we are committed to funding research that accelerates our goal of early detection, prevention and a cure. Thank you for joining in our efforts.

By Ashley Janover

Purple and White Fight Night was set to start at 8pm but when I arrived at the venue and peaked my head around the curtain at 7:45pm there was a line outside the door. I knew in that very moment that the evening was going to be a success.

Every year my advocacy group “Team Hope” throws an annual charity event. I do everything that I can to raise as much funds as possible and entertain the crowd. The term “fight” in Purple & White Fight Night represents a tenacious drive to fight back against a disease that has forever changed our lives. My mother’s name was Betheny Janover and she passed away from Pancreatic Cancer on September 24^th, 2011 at the age of 54. She was diagnosed with Stage 3 Pancreatic cancer and survived a year. Danyelle’s lost her father at 41 years young after a 2 year battle with Lung Cancer.  By raising money for the advancement of research and creating awareness amongst those who do not understand the seriousness of this disease we are making a genuine difference in their memory.

This year the event was a socially conscious fashion show, a concept I truly believe in. I knew that if I wanted to incorporate a fashion show, it would have to be a socially conscious brand. All items must be made in NYC, eco-friendly. We featured designer Daniel Silverstein’s current line. He strives to create a collection that melds his personal design aesthetic with the zero waste design techniques he has developed. At the height of the evening over 200 attendees were enjoying Daniel’s designs, pop-up shops, and a lavish auction & raffle. Dress code: Cocktail Chic!

Right before my partner Danyelle and I gave our speeches we ran into the ladies room and walked in a stall together. We gave each other a big hug, took a deep breath and each exchanged a couple of words about how proud our parents would be if they could see what we had done for them. In that very moment, I knew Danyelle felt all the pain I had experienced over the last 3 years. My friend had also lost her best friend, her father. We understood each other, and I was instantly at ease.

Giving my speech was a particularly extraordinary part of the evening. It was only then when I saw all the faces in the crowd; my friends, family, and everyone who came in from out of town to show their support. I wanted everyone to understand about pancreatic cancer and how unique the Hirshberg Foundation is. At the end, when I thanked my mom I saw everyone’s eyes fill with tears and I thought to myself, “wow, I am not the only who is honoring this woman and I’m certainly not the only one who was in some way affected by this disease.” The moment was powerful and I felt an overwhelming abundance of love and support in that very instant.

My mother was my very best friend and she always told me that through hardships, rejection, and mistakes, success will come. Three years after losing her we’ve succeeded in raising thousands of dollars towards the advancement of research. I remain inspired every day to maintain my relationship and dedication to the Hirshberg Foundation. Moving forward, Purple & White Fight Night will be even larger, include more people, present bigger prizes, and double the money raised for pancreatic cancer!

*Thank you to Daniel Silverstein and sponsors Picks for Peace, Creeds of Love, Canopy Brand Group, The Wild Ivy, and Trusted Nutrients for supporting our philanthropic efforts.