An NCI-designated Comprehensive Cancer Center
By Cara Martinez | October 22, 2019
Prakash Kulkarni Prakash Kulkarni, Ph.D.
Recently, the World Economic Forum revealed 10 breakthrough innovations expected to radically impact global social and economic order in the next five years. Among these developing technologies were intrinsically disordered proteins, or IDPs, a complex area of research with the potential to improve many types of cancer therapies.
 
City of Hope researchers Supriyo Bhattacharya, Ph.D., and Prakash Kulkarni, Ph.D., are at the forefront of this emerging field, blending their backgrounds in computational biophysics and therapeutic research to deliver results in several cancers, including prostate, head and neck, lung cancer and acute lymphoblastic leukemia.
 
Intrinsically disordered proteins are proteins that don’t have a traditional three-dimensional structure. Their purpose serves to provide flexibility for cells to adapt and function; however, this elasticity worsens neurodegenerative illnesses and cancers. Even worse, IDPs make it difficult for drugs to target them.
 
The concept of IDPs is considered a major paradigm shift for molecular biologists like Bhattacharya and Kulkarni, because proteins like these were previously believed to be nonfunctional.

Central Players in Cell Function

“But now we understand that many of these proteins are indeed functional and act as central players in how cells grow and divide,” said Bhattacharya, assistant research professor of translational bioinformatics in the Department of Computational and Quantitative Medicine at City of Hope. 
 
And, more recently, researchers have come to better understand how prevalent IDPs are in the human body.
 
“These proteins are naturally occurring in our bodies,” said Kulkarni, a research professor in the Department of Medical Oncology & Therapeutics Research. “In fact, recent estimates suggest that roughly 50% of the proteins in our cells are IDPs.”
 
Over the last decade, Bhattacharya and Kulkarni have studied the dynamics and structural diversity of IDPs, while also researching how these properties can be used to understand their interactions with other proteins in the body.  
 
“These complex proteins are often considered ‘undruggable,’” said Bhattacharya. “My immediate hope is to change this belief, beginning with nonsmall cell lung cancer.”  

Focusing on Lung Cancer

Nonsmall cell lung cancer is the most common type of lung cancer, accounting for approximately 80-85% of lung cancer cases. There are various forms of the disease, including adenocarcinoma, which commonly develops in people who have never smoked.
 
Although nonsmall cell lung cancer is a key focus for Bhattacharya, he is also studying IDPs in the context of prostate cancer and acute lymphoblastic leukemia.
 
“In each of these diseases, IDPs play a central role in the growth of cancer cells and how they spread throughout the body,” said Bhattacharya. “I develop design principles for therapies that specifically target IDPs using my background in computational methods.”
 
Like Bhattacharya, Kulkarni has been studying IDPs for more than a decade. His efforts center around three key areas of IDP-related research in several diseases, including lung, prostate, and head and neck cancers.
 
Kulkarni’s specific research interests include understanding how IDPs transform a “normal” cell into a cancer cell, how those cancerous cells then take over specific locations in the body, and finally, how those now cancerous cells develop a resistance to drugs and treatments. He also hopes to determine whether these changes can be reversed, which may ultimately shed light on treatment options.
 
“For years, IDPs have been disregarded because of their pliable structure and complex nature,” said Kulkarni.  
 
However, Kulkarni says IDPs do have structure, no matter how subtle.
 
“I think that perhaps structure, like beauty, lies in the eye of the beholder,” he said.
 
Both Bhattacharya and Kulkarni understand that teamwork is required to tackle such a dense and complex area of science. Not only have the two partnered alongside each other on various projects, but they have also relied on the expertise of fellow City of Hope scientists like Ravi Salgia, M.D., Ph.D., the Arthur & Rosalie Kaplan Chair in Medical Oncology; Nora Heisterkamp, Ph.D., a professor in the Department of Systems Biology; and Nagarajan Vaidehi, Ph.D., professor and chair of the Department Computational and Quantitative Medicine, to bring their ideas to light.
 
“We focus on a highly interdisciplinary approach to tackling IDPs,” said Kulkarni. “We are working alongside collaborators who are experts in their respective fields to employ techniques like nuclear magnetic resonance, virtual drug screening and theoretical prediction algorithms.” 
 
If successful, Bhattacharya, Kulkarni and their cross-functional team’s methods will better predict properties of these proteins and better address patient-specific aspects of the diseases, including drug resistance and alternative therapies.
 
“Drug discovery in this area is both promising and extremely challenging,” said Bhattacharya. “But our ultimate goal is to use IDPs to save lives and extend longevity — and I trust we will get there in the coming years.”
 

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