RESEARCH

UMKC Researcher Targets Key Cancer Pathway

Mukherji inside his lab at the School of Pharmacy.

In many cancers, tumor cells depend on the same process the body uses to adapt to low oxygen. That process — known as the hypoxia-inducible factor (HIF) pathway — helps tumors grow blood vessels, spread and resist treatment.

At the School of Pharmacy, Mridul Mukherji, D.Phil., associate professor, is working to interrupt that process.

“We are focusing on preventing cancer growth,” Mukherji said. “Pretty much all solid tumors will undergo this HIF pathway.”

His research focuses on developing new compounds that block the HIF pathway earlier and more completely than existing therapies, an approach that could improve how kidney cancer is treated.

And his distinguished work reflects the level of research already underway at UMKC, which last year was recognized with the prestigious Carnegie Research 1 classification.

Targeting a Fundamental Cancer Process Under normal oxygen conditions, cells tightly regulate HIF activity. The pathway is controlled by the von Hippel-Lindau (VHL) protein, and prevents angiogenesis, which is the formation of new blood vessels.

But when oxygen is scarce, the HIF pathway is triggered, and genes that promote angiogenesis, metabolism and cell survival are activated. While this response helps normal tissues adapt to low oxygen, it becomes dangerous in cancer.

In renal cell carcinoma, the most common form of kidney cancer, mutations in the VHL gene prevent proper regulation of HIF. The pathway remains switched on even when oxygen is available, driving continuous blood vessel formation.

“When hypoxia has triggered the formation of new blood vessels, tumors are getting enough supply of nutrients and oxygen for it to divide rapidly and metastasize,” Mukherji said.

With support from a $275,000 research grant, Mukherji’s lab is testing compounds designed to stop this pathway using a new approach.

“We have designed some molecules that inhibit the HIF pathway and got a grant to test these compounds in renal cell carcinoma,” Mukherji said. “The kidney plays a major role in sensing oxygen.”

Blocking HIF Further Upstream Many current cancer treatment drugs limit tumor blood supply by blocking the vascular endothelial growth factor (VEGF), a protein made downstream during HIF pathway activation.

“The issue with this is it’s only partially effective because there’s actually only one of many proteins involved,” Mukherji said.

By contrast, Mukherji and his lab aim to target the pathway earlier in the process, before angiogenesis is fully activated.

“We are targeting the HIF pathway further upstream, where if we block it, it will have a much wider effect than just inhibiting VEGF protein,” Mukherji said.

Because angiogenesis is essential for metastasis, blocking this process could significantly alter disease outcomes.

“Most cancer patients die because of metastasis, not because of the primary cancer,” Mukherji said. “So, if we are able to block angiogenesis, and therefore hopefully metastasis, then we are blocking a critical process for cancer development or cancer spread.”

"The quality of life for cancer patients who undergo chemotherapy is very, very sad. If in any way I can contribute to changing that, it would be a huge satisfaction."

MRIDUL MUKHERJI, D.PHIL.

Dr. Mukherji explains a concept to two students while standing inside his lab.

Mukherji makes time outside of his research to mentor Ph.D. students like Abhinuv Viswanathan (center) and Gauresh Shivji.

Improving Cancer Therapy Options Mukherji’s work also addresses a longstanding problem in oncology: treatment-related side effects.

“Most of the cancer drugs inhibit the growth of rapidly dividing cells,” Mukherji said. “That’s why patients undergoing chemotherapy will have hair loss, suppressed immune systems or gastrointestinal tract problems.”

Mukherji hopes that focusing on the pathway central to tumor survival could lead to treatments that are both more precise and less harsh for patients.

Although his current research focuses on kidney cancer, Mukherji believes the implications could extend much further.

“All solid tumors go through this pathway,” he said. “We just started work with pancreatic cancer. That’s a very aggressive cancer with a lot of drug resistance and immune suppression, and the HIF pathway is a major pathway responsible for that.”

Research With a Purpose Mukherji’s interest in the HIF pathway dates back to his doctoral training at the University of Oxford, where he helped identify enzymes involved in the process known as hydroxylases.

Since joining UMKC in 2007, Mukherji has enjoyed splitting his time teaching and conducting HIF pathway research.

“Students bring new, fresh ideas better than what we have thought of,” he said. “Science is developing very fast, and students will be our future.”

According to Gerald Wyckoff, Ph.D., director of research administration for the School of Pharmacy, what makes Mukherji’s research stand out is the real-world impact it may have.

“Ultimately, the work he's doing is going to have a clinical impact on people who are experiencing some of these diseases where hypoxia-inducible factor is playing a role,” Wyckoff said. “These are novel factors that would be clinically relevant because they could lead to new drugs.”

For Mukherji, the motivation behind his research remains deeply personal. He has watched friends and loved ones struggle through chemotherapy and seen the toll it takes on daily life.

“The quality of life for cancer patients who undergo chemotherapy is very, very sad,” he said. “If in any way I can contribute to changing that, it would be a huge satisfaction.”

Left: Cytiva AKTA start chromatography system. Right: Biorad ChemiDoc MP Imaging System.

Endowed Chair Funds Help Researcher with Cancer and Aging Research

Kun Cheng, Ph.D., is the Sperry Family Fund Endowed Chair in Geriatric Pharmaceutical Research at the School of Pharmacy.

As a professor at the School of Pharmacy, the research of Kun Cheng, Ph.D., is focused on developing new drug delivery systems and therapeutic strategies to improve treatments for cancer, liver diseases, Alzheimer’s disease and other age-related conditions. Cheng is the Sperry Family Fund Endowed Chair in Geriatric Pharmaceutical Research and a Curators’ Distinguished Professor.

His recent progress includes earning a U.S. patent for a novel anti-PD-L1 peptide that can potentially be used for cancer immunotherapy and diagnosis. Cheng’s work also has promising implications for pancreatic cancer, a disease that is often detected late and difficult to treat.

Cheng credits the Sperry Family’s endowed chair for fueling much of this progress.

“The endowed chair has provided stability, resources and the freedom to pursue ambitious research that will make a lasting impact,” Cheng said. “Because of the support, we are able to devote more time to developing new therapies for Alzheimer’s disease, designing delivery systems that can cross the blood-brain barrier, exploring innovative ideas and collaborating with colleagues in ways that enrich both my work and the broader academic community.”

Mentorship is also central to Cheng’s impact. Recently, he graduated four Ph.D. students and trained one postdoctoral fellow. Graduates now serve in faculty roles at pharmacy schools, including one at Washington University as a postdoctoral researcher and another at Memorial Sloan Kettering Cancer Center as a clinical chemistry fellow. One recent graduate, John Fetse (Ph.D. ’22), is now a tenure-track professor at Binghamton University and recently published research on PD-L1 for cancer immunotherapy.

This work is possible because of the generosity of the late Robert Sperry, who wished to establish this fund, and his mother, Ruth, who ensured UMKC received the support after his passing. Sperry was a longtime friend and supporter of the School of Pharmacy.