The University of Cincinnati’s Syed Ahmad, MD, is the national principal investigator for the phase 2 Southwest Oncology Group (SWOG) 2104 trial.

Ahmad said he began work on this project several years ago in collaboration with Heloisa Soares, MD, PhD, of the University of Utah, through their collaboration as members of the cooperative SWOG Cancer Research Network.

The trial focuses on patients with pancreatic neuroendocrine tumors. The current standard of care for these patients is surgery only, followed by observation, but a subset of patients are at high risk for their cancer to return, Ahmad said.

“In the past, we would just watch and wait as no studies had proven beneficial to prevent recurrence," said Ahmad, University of Cincinnati Cancer Center co-director and professor of surgery in UC’s College of Medicine. “However, there was a recent study in patients with advanced cancer showing the efficacy of chemotherapy drugs capecitabine and temozolomide. So we proposed and opened this combination of drugs in patients who have had surgery but are at high risk of recurrence.”

In the trial, patients who have had pancreatic neuroendocrine tumors surgically removed will be randomized to two study arms. Select patients will either receive the two chemotherapy drugs or a placebo.

“The primary endpoint is to see if we can prevent recurrence of the cancer,” Ahmad said. If the treatment regimen proves successful, it could lead to improved survival rates for these patients, he said.

The study has just opened at UC and aims to enroll 150 patients at sites throughout the country. Ahmad said being part of the SWOG Cancer Research Network helps advance research and patient care.

“It allows us to open studies at hundreds of sites to help with trial enrollment,” he said. “It allows us to open novel studies from other institutions so that our local patients have access to cutting edge therapy.”

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A new clinical trial is testing the effectiveness of chemotherapy treatment following surgery for a subset of pancreatic cancer patients.

New Trial Tests Chemotherapy Regimen Following Pancreatic Cancer Surgery

Enzyme shows promise as target to treat HPV negative head and neck cancer

Vinita Takiar’s lab in UC’s Department of Radiation Oncology studies how to improve radiation therapy for head and neck cancer patients.

Julianna Korns, a doctoral student working in Takiar’s lab, and her colleagues study an enzyme called Plk1 that allows healthy cells to divide and function normally. When overexpressed in head and neck cancer cells, it causes the cells to divide abnormally and at a faster rate, leading to the accumulation of more cancer cells.

Using data from The Cancer Genome Atlas database, the research team found Plk1 overexpression was correlated with worse survival outcomes in head and neck cancer patients. Studying cell lines in the lab, they found blocking Plk1 reduces head and neck cancer cell growth.

Interestingly, Korns noted that Plk1 inhibition reduces cell growth in head and neck cancer cells that are positive and negative for HPV, but HPV-negative cells are more sensitive to this treatment than HPV-positive cells.

“Typically, HPV-negative head and neck cancer patients are more resistant to therapy, so this novel finding could provide benefit to HPV-negative head and neck cancer patients in the clinic,” Korns said. “Our study indicates a potential marker for treatment outcomes. Understanding the role of Plk1 is pivotal to optimizing treatment regimens for these patients.”

Korns said the team plans to translate its preclinical findings into clinical settings, targeting Plk1.

“Our findings may provide a novel target for head and neck cancer therapy in combination with radiation, implementing the bench to bedside mentality to improve patient outcomes and reduce toxicities related to current treatments,” she said.

Plk1 signaling as a therapeutic target for HPV-head and neck cancer was presented by Korns April 17 from 1:30-5 p.m. during the Radiosensitizers and Radio-immunomodulators poster session. Co-authors include Takiar, Trisha Wise-Draper and Samuel Thompson.

Protein a potential new target for breast cancer treatment

Researchers in Jun-Lin Guan’s lab in UC’s Department of Cancer Biology found a potential combination treatment target for breast cancer cells and breast cancer stem cells.

Kanakaraju Manupati, PhD, postdoctoral fellow in Guan’s lab, researched a protein called NuMA1. The protein is known to be upregulated in breast cancer, but the specific role it plays within tumors of breast cancer subtypes was not well-defined.

Manupati’s research found that when NuMA1 was deleted in animal models of three different breast cancer cell lines, it reduced tumor growth. Removing NuMA1 from breast cancer stem cells led to reduced metastasis, or cancer spread, suggesting it plays a role in cancer growth and spread in both breast cancer bulk and stem cells.

“The interesting finding is that we observed that NuMA1 depicted various roles in different subtypes of breast cancer,” he said.

There are currently no drugs that directly target NuMA1, but it is regulated by an enzyme called PIM1. The research team tested the effectiveness of a drug that blocks PIM1 and found the enzyme inhibitor reduced tumor formation and cancer spread in all three subtypes of breast cancer they tested.

The treatment was even more effective when combined with an autophagy inhibitor that blocks the cell's process of breaking down nutrients to grow and thrive.

“When we used this combination approach, we could see there is a significant reduction of breast cancer tumor formation as well as metastasis,” Manupati said.

The knowledge that NuMA1 plays a role in both bulk breast cancer cells and breast cancer stem cells makes it a promising potential target, Manupati said.

“To prevent breast cancer metastasis, we need to kill both breast cancer cells as well as breast cancer stem cells,” he said. “Therefore, we need to target both of these populations to fully prevent breast cancer.”

Moving forward, Manupati said the team hopes to continue studying the potential applications of the therapy approach of using a combination of PIM1 and autophagy inhibitors and how NuMA1 works in a variety of breast cancer stem cells.

Role of NuMA1 in tumor formation and metastasis with implications for combination therapy of PIM1 and autophagy inhibition in breast cancer was presented by Manupati April 19 from 9 a.m.-12:30 p.m. during the Cancer Stem Cells and Therapeutic Resistance poster session. Study co-authors include Guan, Mingang Hao, Michael Haas and Syn Kok Yeo.

Research finds oncogene overexpressed in head and neck cancer

Susan Waltz, PhD, studies the role of a gene that helps accelerate cancer growth called Ron in her laboratory in UC’s Department of Cancer Biology. Zhixin Lu, a doctoral student in Waltz’s lab, wanted to learn more about how Ron affects head and neck cancers while on a rotation in Takiar’s lab.

Lu’s research bridges a collaboration between the Takiar and Waltz laboratories and between UC departments.

“We have heavily studied this Ron receptor in breast cancer and prostate cancer, how it drives cancer metastasis and drug resistance,” Lu said. “Ron is heavily expressed in a lot of cancers, including head and neck cancer, but we know much less about its role in head and neck cancer. So that’s really the premise of my project.”

Lu’s research found that Ron is overexpressed at high levels in multiple cell lines of head and neck cancer, which she said indicates it may play a role in the cancer cells’ function and growth.

“Ron expression is correlated with worse patient survival outcomes and radiation resistance. The higher Ron is expressed, the less the patient is going to survive in terms of overall survival, which indicates it potentially has a very negative role in those patients,” Lu said. “This makes it a very promising target to study.”

A protein called EGFR is also overexpressed in a majority of head and neck cancers, but anti-EGFR treatments have not been very effective to this point due to the cancers developing drug resistance. Interestingly, the researchers found there is an inverse correlation between Ron and EGFR expression in head and neck cancer cell lines and patient data.

Future studies will aim to learn more about how EGFR and Ron interact and whether blocking Ron will make EGFR-targeted treatments more effective. Lu said the team is also looking to see if there is a similar inverse correlation between Ron and EGFR in breast cancer, which could provide more information on their interaction.

As researchers learn more, Lu said Ron inhibitors could potentially become a more common treatment option for head and neck cancer patients. Current treatments still rely heavily on chemotherapy and radiation, which come with toxicity and side effects, but a small molecule target like Ron could reduce the dose of chemotherapy needed, she said.

“It’s more precise because the small molecule really targets proteins and the oncogenic pathway, and combined with that, may not only reduce the side effect but also be more precise to the specific target,” Lu said.

RON receptor tyrosine kinase in head and neck cancer: a potential target for overcoming resistance to anti-EGFR therapy was presented by Lu April 16 from 1:30-5 p.m. during the Drug Resistance in Molecular Targeted Therapies 1 poster session. Co-authors on the project include Mathieu Sertorio, Takiar and Waltz. 

Other abstracts being presented by Cancer Center researchers include:

FOXA2 induces invasive mucinous adenocarcinoma of the lung in the presence of mutant KRAS, presented by Yutaka Maeda April 17 from 9 a.m.-12:30 p.m. during the Gene Regulation in Solid Tumors poster session.

Pan-cancer splicing analysis reveals shared drivers of malignant transformation and survival, presented by Anukana Bhattacharjee April 17 from 1:30-5 p.m. during the Bioinformatics Applications in Cancer Biology 2 poster session.

Role of her3 v104l mutation on tumor growth and her3 stabilization, presented by Rosalin Mishra April 18 from 9 a.m.-12:30 p.m. during the Identification of Molecular Targets 1 poster session.

RON receptor signaling enhances prostate cancer metastasis in Hi-Myc mice, presented by Angelle D. Jones April 17 from 9 a.m.-12:30 p.m during the EMT and Plasticity poster session.

Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer, presented by Andrew Waters April 16 from 1:30-5 p.m. during the Precision Molecular Subtyping and Therapeutic Development poster session.

The role of HER3 mutations in the progression of colon cancer and modulation of drug sensitivity and resistance, presented by Mary K. Kilroy April 18 from 9 a.m.-12:30 p.m. during the Oncogenes and Tumor Suppressor Genes as Targets for Therapy 3 poster session.

University of Cincinnati Cancer Center researchers presented more than a dozen abstracts at the 2023 American Association for Cancer Research Annual Meeting, including findings that could advance treatments for head and neck and breast cancers.

Head and Neck, Breast cancer Research Highlights AACR Abstracts

Pancreatic cancer diagnoses are increasing more rapidly than any other cancer type while remaining one of the most deadly cancers.

The American Cancer Society estimates approximately 64,000 Americans will be diagnosed with pancreatic cancer this year, and approximately 50,500 people in the U.S. will die of pancreatic cancer in 2023. While currently the third-leading cause of cancer death in the United States, pancreatic cancer is expected to become the second-leading cause of cancer death by 2030, highlighting the need for new and innovative treatments.

More than 90% of pancreatic cancers are driven by mutations in a certain gene called KRAS. The National Cancer Institute (NCI) has announced an intent to fund research from the University of Cincinnati’s Andrew Waters, PhD, to better understand how to overcome treatment resistance and develop better treatments for KRAS-mutated pancreatic cancer.

In healthy human cells, the KRAS gene acts as a “light switch” telling cells when to divide.

“In the on position, cells divide. In the off position, cells stop dividing. It is tightly controlled, regulated, and balanced,” said Waters, University of Cincinnati Cancer Center researcher and assistant professor in the UC College of Medicine’s Department of Surgery, Division of Surgical Oncology and Department of Cancer Biology. “When you have a mutation in KRAS, the light switch can’t be turned off, and cells divide uncontrollably. If left unchecked, this can lead to pancreatic cancer.”

The KRAS gene mutations were discovered more than 40 years ago, but it was considered not able to be treated by drugs, or “undruggable,” for decades. Drawn to difficult problems, Waters said the challenge of KRAS appealed to him as an area where he could make a difference.

“Initially when I heard almost all pancreatic cancers had a mutation in the KRAS gene, and it was undruggable, this seemed like somewhere I could potentially contribute,” he said. “As I learned more and more about KRAS, it became a passion of mine, and now I am hooked.”

The Food and Drug Administration recently approved the first two drugs that target one particular KRAS mutation, but the drugs have a limited use in pancreatic cancer. While the KRAS mutation that the drugs target is common in lung cancers, it is rare in pancreatic cancers.

“About 98% to 99% of KRAS-mutant pancreatic cancer patients have other KRAS mutations and will not benefit from this class of drugs,” said Waters. “We need KRAS drugs that target the KRAS mutations that occur in pancreatic cancer.”

The recently approved KRAS drugs are also limited because like with all targeted therapies, the cancer cells eventually develop resistance to the targeted treatment, Waters said.

“Because we know relapse will occur, we need to identify the resistance mechanisms in pancreatic cancer that drive the relapse in order to develop KRAS inhibitor combination approaches,” he said.

The NCI intends to fund Waters’ lab through an approximately $587,000, three-year career development grant. With the funds, Waters will test clinically relevant drugs that target two particular KRAS mutations more commonly found in pancreatic cancer. The drugs being tested are novel, unpublished formulations that will be studied both through cell lines and animal models.

Waters will also study the specific mechanisms within KRAS-mutated pancreatic cancer cells that lead to resistance to targeted treatments. Some of these processes may be similar to resistance processes found in KRAS-mutated lung cancer cells, but Waters said there is growing evidence that each mutation is different.

“Until somewhat recently, almost everyone thought all KRAS mutations are equal,” he said. “I hypothesize different mutations will have some distinct resistance mechanisms. In the era of personalized medicine, this is extremely important, because understanding these mutation-specific resistance mechanisms can potentially guide treatment options in a personalized way.”

With more knowledge on what drugs effectively treat KRAS-mutated pancreatic cancer and what causes drug resistance, the goal is to increase the efficacy and longevity of KRAS-targeted treatments for pancreatic cancer patients.

As his work continues, Waters said he continues to be motivated by pancreatic cancer patients, volunteer work with organizations like the Pancreatic Cancer Action Network and the personal effect cancer has had on his life.

“I have lost many family members and close friends to cancer, and some of those people that I lost have been my biggest supporters,” he said.

Waters said his path to joining UC’s faculty has been unconventional, including work at biotech companies and conducting his doctoral research at the Frederick National Laboratory for Cancer Research.

“National laboratories are funded by the federal government so there isn’t a big push to apply for grants and secure additional external funding,” he said. “To receive the best possible score on my first independent grant application from the NCI, arguably the most competitive division of the National Institutes of Health, feels very validating.”

Read about additional pancreatic cancer research at UC led by Krushna Patra.

Pancreatic cancer diagnoses are increasing more rapidly than any other cancer type while remaining one of the most deadly cancers. 

University of Cincinnati Cancer Center

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