Tag: Shinde

For Pancreatic Cancer Awareness Month, we sat down with Rahul S. Shinde, D.V.M., Ph.D., assistant professor in Wistar’s Ellen and Ronald Caplan Cancer Center who researches potential new therapies for treatment-resistant cancers like pancreatic cancer.

Why is pancreatic cancer so deadly and prognosis so poor, with only about 13% of people diagnosed going on to survive the next five years?

Actually, although we now have a 13% 5-year survival rate that may seem low, it nevertheless represents a vast improvement over what the outlook used to be. Just a few decades ago, that 13% was closer to 5%. We know that significant improvements are possible, but we urgently need to improve clinical outcomes.

Pancreatic cancer poses a large threat for a few reasons. 

1. Pancreatic cancer tends to be diagnosed at later stages. A tumor in an internal organ is not immediately apparent in the same way that, for example, a suspicious mole might be, and surgery at those later stages — which is not always an option — tends to have a lower success rate.
   
   
2. Pancreatic cancer develops very stubborn resistance to therapy.

 In my lab, we’re focused on understanding how we might develop new therapies by investigating the gut microbiome.

What role does the gut microbiome play in pancreatic cancer?

The gut microbiome, which is a shorthand term for all the diverse microbes, bacteria, etc. that are present within the intestinal tract, can influence different systems throughout the body, including tumors. Tumors are the ultimate biological survivors: they are constantly looking for ways to improve their capacity to grow.

As signals from the gut microbiome travel throughout the body, tumors can incorporate any signals that might be to their advantage.  We are focused on identifying key microbial signals that indirectly contribute to enabling a hospitable environment for pancreatic cancer to grow

Does that mean that diet plays a role in cancer risk?

Yes, we think diet plays a role.  A key question is how what we eat or drink alters the microbial environment. That may sound like a simple question, but it’s actually quite complicated; for example, if you drink a cup of coffee right now, the composition of your gut microbiome will be drastically different in an hour than if you hadn’t.

Now apply that complexity to everything that every person eats or drinks. We each carry vastly different and constantly changing microbial genomes. Even though the genome of every human on Earth is 99% identical, the composition of the microbiome from person to person can vary as much as 80% or 90%.

Our lab focuses on interventions that impact the crosstalk between pancreatic cancer and the gut microbiome. That intervention could be a diet change; a microbiome-targeted therapy; or disruption of the cancer’s metabolism so it doesn’t benefit as much from microbial proteins.

By identifying which signals from the gut microbiome can cause cancer to benefit or harmful immune cells to proliferate in the tumor, we can develop strategies to disrupt those cancer-causing signals.

You mentioned harmful immune cells in tumors as a problem in pancreatic cancer. But don’t immune cells kill cancer?

Like almost everything in biology, whether immune cells are good or bad for cancer depends on the context. When cancer starts to grow, the immune system responds by sending macrophages to fight the cancer — and that is a good thing.

But if a tumor has developed, that means the immune system’s first line of defense has already failed. By that point, the macrophages in and around the tumor have stopped hindering it and have begun to help the tumor.

Tumor-associated macrophages can be thought of almost like traitors: instead of fighting cancer, they have been reprogrammed to help the cancer grow and resist treatment. That reprogramming process can be sped up or worsened by harmful signals from the gut microbiome, which is what we aim to stop.

What makes you hopeful about the future of pancreatic cancer research?

I’m hopeful for our ability to fight cancer because, more than ever before, researchers are armed with access to data of a quantity and quality that would have been unimaginable years ago. With modern analysis techniques — from genome-wide analysis to wide-ranging bioinformatics support — we are beginning to find patterns within the noise. Science is only becoming more collaborative. I’m confident that, working together, we can assemble the pieces of the cancer puzzle.

Wistar’s Dr. Rahul Shinde with PanCAN’s Nick Pifani and Bruce Platt Rally Around Common Bond

Meet Nick Pifani who came to Wistar to share his story of surviving pancreatic cancer; he was one of several in his family who faced pancreatic cancer and won the battle. Bruce Platt, PanCAN volunteer advisory board member, lost his mother to pancreatic cancer. Nick and Bruce met Wistar’s Dr. Rahul Shinde, a 2022 PanCAN Career Development Award recipient, to learn more about his promising pancreatic cancer research.

“We want to tell the great stories—about the doctors that save lives and the researchers that ultimately bring new drugs, therapies and standards of care to patients,” said Nick. “We also want to tell positive stories of survival.”

Nick and Bruce are Philadelphia ambassadors for the local PanCAN cause, they connect cancer survivors with resources while building awareness and understanding. Pifani and Platt both see the need for a paradigm shift on how patients process a pancreatic cancer diagnosis as well as help the public to understand that pancreatic cancer can be treated effectively.

“My mother was diagnosed in 2004. I became a caregiver in 2006. She passed in 2009—she almost made five years,” said Bruce. “Back then, there were no real treatment options. The doctor basically said to my mother, ‘Go get your affairs in order,’—can you imagine the shock of that?”

When Bruce’s mother passed, he wanted to be her voice and in 2010 went to his first PanCAN meeting. Every year he’s become more involved. Bruce’s passion for the cause led to political action and making headway on pancreatic cancer awareness and support with legislators like Congressman Brendan Boyle and U.S. Senator Bob Casey. Along the way Bruce met many people diagnosed and fighting pancreatic cancer who ultimately became his friends. “I’ve met and become close to amazing people, but you can also get to a point where you think, I’ve done everything I can do. But if I ever get near that point, someone usually calls me and says, ‘So-and-so has it’ and it pumps me back up. So, I go back and fight some more. I’m in this until the day I die.”

When Nick was diagnosed with pancreatic cancer he wasn’t interested in the standard of care. “I knew what the standard of care did for about everybody else and I didn’t want to go down that route because I knew where it would end. Fortunately for me, I had doctors who found genetic mutations and understood I would have better success with different types of chemotherapy and radiation.”

Nick’s hope is that research and treatments progress to where a person diagnosed with pancreatic cancer has more options. “The disbelief and horror that happens when you are diagnosed, will be followed with, ‘We have four different treatment options, they’re effective and have an 80% or 90% cure rate. Which flavor do you want?’ Hopefully, Bruce and I will be around to see that.”

That day isn’t here yet, but Wistar scientists are working to make it happen. Nick and Bruce met with Dr. Rahul Shinde, one of Wistar’s resident pancreatic cancer researchers.

Dr. Shinde’s research is in one of the hottest areas of science and focuses on how the gut microbiome impacts immune cell function — those immune cells’ ability to fight cancer. He hopes to pave the way for future gut-bacteria-based therapies in the hopes of improved pancreatic cancer patient survival.

Dr. Shinde studies how macrophages — specialized cells that act as a front-line defense system for our immune systems — alter the pancreatic cancer tumor microenvironment which plays a key role in how the cancer develops, progresses, and reacts to therapies. “The successful outcome of this research may form the basis for gut bacteria-based therapies or diet-based therapies to improve the survival as well as the quality of life of pancreatic cancer patients,” he said.

“If you’re going to get sick, Philadelphia is a good place to be because we have the best doctors and researchers in the world,” said Bruce. “I have a big mouth. I’ll fight for more and more research money and more and more exposure. Did you know Jack Benny, Joan Crawford, Michael Landon, Patrick Swayze, Steve Jobs, and Alex Trebek all died of pancreatic cancer? My mother always said we need to get a celebrity behind us to tell this story. I don’t plan to quit telling all the stories I have anytime soon.”

More than 1,000 supporters gathered in Fairmont Park for PanCAN PurpleStride Philadelphia 2023 to support the Pancreatic Cancer Action Network (PanCAN). Wistar’s Dr. Rahul Shinde is a PanCAN research grant recipient, and our lab was honored to attend the event and represent the scientific community. People of all ages wore purple to show support with many teams commemorating loved ones lost. I, too, walked in memory of a good friend and uncle who both lost their battles with pancreatic cancer. 

The atmosphere was emotional and inspiring as we heard from a 19-year survivor who described his journey through treatment and recovery. The 5-year survival rate has increased from 10% to 12% in the last few years due in part to PanCAN research and funding. It is their goal to reach a 20% survival rate by 2030.

PanCAN PurpleStride Philadelphia raised over $600,000 with 60 similar events held nationwide. The funds support services for patients and their families, along with research grants to improve early detection and treatment of pancreatic cancer. The Shinde Lab raised more than $1,000 thanks to the support of family and friends. 

Walking among this Philadelphia community of supporters reminds us all of our responsibility to make our research count. PanCAN PurpleStride Philadelphia was a realization of how meaningful our work is. There is heartbreak surrounding pancreatic cancer, but also considerable hope in scientific advancement. 

Notes From the Field Series is written by a member of Wistar’s scientific community and reflects on life, both in and out of a busy biomedical research lab. SK Reiser is a graduate student in the lab of Dr. Rahul Shinde.

The team identified the metabolite TMAO drives immune activation in the tumor microenvironment and boosts response to immune checkpoint blockade therapy in pancreatic cancer.

Rahul S. Shinde, D.V.M., Ph.D., Assistant Professor in the Immunology, Microenvironment, and Metastasis Program of Wistar’s Ellen and Ronald Caplan Cancer Center and the Institute’s inaugural Caspar Wistar Fellow published evidence in Science Immunology of a therapeutic target in the gut microbiome for pancreatic cancer.

Recently awarded the Pancreatic Cancer Action Network Career Development Award, Shinde focuses his research efforts on understanding the gut microbiome and identifying potential targets for cancer therapies. In this newly published paper, Shinde and his collaborators reveal that a metabolite derived from a gut microbe called trimethylamine N-oxide (abbreviated TMAO) boosts immunity against tumors by triggering immune activation in pancreatic cancer. Furthermore, the study provides evidence that targeting TMAO production in the gut microbiome could improve the efficacy of immune checkpoint blockade (ICB) therapy for the disease.

Pancreatic cancer is a particularly deadly disease with a tumor microenvironment that aggressively suppresses immune response. Immunotherapies can be improved by boosting immune activation in the tumor microenvironment – a function influenced by the gut microbiome. In the study, the researchers administered TMAO and observed effects on tumor growth and immune response in the tumor microenvironment. They found evidence that TMAO stimulated action from immune cells such as macrophages and T cells as well as increased pancreatic cancer’s responsiveness to ICB therapy, ultimately boosting the body’s ability to identify and attack cancer cells.

“With growing interest in selective targeting of the gut microbiome to improve cancer treatments, this study can create a new paradigm for discovering novel gut microbial metabolites influencing anti-tumor immunity and inform innovative treatment strategies for highly lethal and hard-to-treat pancreatic cancer,” says Shinde, corresponding author on the paper.

He elaborates that his findings raise a series of questions with clinical implications, including what sources of TMAO confer its anti-tumor effects and whether this beneficial TMAO can be achieved by altering these sources. Additionally, he emphasizes that potential future directions of this work could delve into understanding whether TMAO can promote anti-tumor immunity in other cancer types with treatment resistance.

Shinde collaborated with fellow Wistar principal investigators Chi Van Dang, M.D., Ph.D., Aaron Goldman Ph.D., Hsin-Yao Tang Ph.D., Noam Auslander, Ph.D., Mohamed Abdel-Mohsen, Ph.D., and Andrew Kossenkov, Ph.D. on this study.

This work was generously supported by the following: NIH, the W. W. Smith Charitable Trust, 2022 Pancreatic Cancer Action Network Career Development Award, Grant Number “22-20-SHIN,”, the Tobin-Kestenbaum families, as well as the Caspar Wistar Fellowship Program at The Wistar Institute.

The Pancreatic Cancer Action Network announced that Rahul S. Shinde, D.V.M., Ph.D., Assistant Professor in the Immunology, Microenvironment & Metastasis Program of Wistar’s Ellen and Ronald Caplan Cancer Center, was bestowed the Pancreatic Cancer Action Network Career Development Award.

Shinde was the Institute’s first Caspar Wistar fellow and was promoted to assistant professor at the start of 2022. He describes his experience as a researcher as “wonderful” and “one in which I have developed personally and professionally” – crediting the collaborative atmosphere and scientific environment at Wistar as excellent support in helping to garner his lab funding. Currently, Shinde is working on characterizing the gut microbiome and host metabolism in the context of immune responses to cancer.

“Growing as a researcher at Wistar is an amazing feeling filled with learning, discovering, and sharing science,” he says, adding that receiving this award at this stage in his research career is an honor. “The PanCAN Career Development Award is a gratifying experience that reassures me that I’m conducting impactful research in my laboratory.”

The $250,000 in grant funding will help propel forward his scientific focus on characterizing how gut microbe-derived metabolites impact immune cell function and support foundational research into a potential supplementary therapy for pancreatic cancer. Shinde elaborates, “The successful outcome of this research may form the basis for gut bacteria-based therapies or diet-based therapies to improve the survival as well as the quality of life of pancreatic cancer patients.”

Research supported by the 2022 Pancreatic Cancer Action Network Career Development Award, Grant Number “22-20-SHIN.”