- Author: Kathy Keatley Garvey
A drug candidate discovered and developed decades ago in the laboratory of UC Davis distinguished professor Bruce Hammock may help control the body's raging and often deadly inflammatory response to chemotherapy treatments, especially for pancreatic and liver cancer patients.
A 16-member international research team, based in the laboratories of Dipak Panigrahy of Harvard Medical School and Hammock, announced the findings in a newly published paper in the journal Proceedings of the National Academy of Sciences (PNAS).
Working in rodent models of liver and pancreatic cancer, they found that they could use a combination of two drugs to reduce inflammation following chemotherapy. Inflammation associated with debris from dying tumor cells can trigger metastasis, the spread of cancer throughout the body.
“We discovered that we can reduce or clear the chemotherapy-generated inflammation by inhibiting or blocking the enzyme, soluble epoxide hydrolase (sEH), and the EP4 prostaglandin receptor,” said co- senior author Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. He is a member of the National Academy of Sciences.
“Basically, when we blocked both the sEH and EP4 eicosanoid pathways, the compounds worked together, preventing pancreas and liver cancer metastasis by stimulating the clearance of debris from prior cancer treatment,” said co-senior author Panigrahy, a physician-researcher with the Israel Deaconess Medical Center, Harvard School of Medicine.
“INV-1120 is a highly potent and selective EP4 antagonist currently in a Phase I clinical trial in the United States (Texas),” said co-senior author Yongkui Sun, chairman of Ionova Life Science, a biotechnology company in China that translates basic biomedical research discoveries into novel therapeutics for cancer. “It demonstrated monotherapy effect and strong synergy with anti-PD-1, the sEH candidate or gemcitabine in fighting cancers such as pancreatic and liver cancers in preclinical animal models.”
Lead author of the paper, “Eicosanoid Regulation of Debris-Stimulated Metastasis,” is Jianjun Deng, a Harvard Medical School researcher. “Chemotherapy results in excessive inflammation and a cytokine/lipid storm caused by the human body's reaction to this pancreatic cancer therapy,” he said. “The debris increases the sEH and EP4 proteins, which trigger a macrophage-derived storm of pro-inflammatory and pro-angiogenic lipid autacoid and cytokine mediators.”
“Controlling the body's inflammatory response to chemotherapy will likely be important to prevent metastasis,” Hammock said. “It hit me that what we really need to do is not so much block cytokines as to move upstream to modulate them and resolve them rather just block inflammation.”
“One way to modulate cytokines is to regulate the upstream eicosanoid pathways including sEH and EP4. The current discovery showed a very nice example by holistically modulate the eicosanoids to prevent pancreatic cancer and metastasis,” said co-lead author Jun Yang, a research scientist in the Hammock lab.
Sun said that “Among many of the insidious characteristics of cancer, cancer uses its dying cells to ‘train' the immune system to create a tumor microenvironment more favorable for its survival. Dying cancer cells can trigger inflammatory responses and release of cytokines, many of which are pro-tumor growth. Cancer uses this ‘positive feedback cycle' to combat cancer therapies, rendering them less effective.”
Other co-lead authors of the paper, are Haixia Yang, a researcher at China Agricultural University, Beijing China; and Victoria Haak, a first-year medical student at the University of Buffalo. At UC Davis, Hammock lab researchers also include Sung Hee Hwang, who made many of the compounds.
Hammock and Panigraphy described the research as a “novel but simple and effective approach.” Combining drugs to block the sEH and EP4 pathways is a novel approach to turning down the inflammation and preventing the cytokine storm caused by chemotherapy and even tumor resection, they said.
“We can increase the concentration of natural pro-resolving mediators termed EETs which act on a biological system to produce other pro-resolution mediators which modulate inflammation and actively resolve the process,” Hammock explained.
Hammock founded the UC Davis-based EicOsis Human Health LLC to bring the inhibitor to human clinical trials, now underway in Texas. “Since this soluble epoxide hydrolase inhibitor acts upstream to down-regulate the eicosanoid and the cytokine storm,” he said, “we are optimistic that it can help patients.”
“The techniques developed and used in this publication have tremendous potential to translate to the clinic,” said Panigrahy.
ACS estimates 42,230 new cases (29,890 in men and 12,340 in women) will be diagnosed this with primary liver cancer this year. About 30,230 people (20,300 men and 9,930 women) will die of these cancers. “Liver cancer incidences rates have more than tripled since 1980, while the death rates have more than doubled during this time,” according to an ACS cancer site.
The Hammock-Panigrahy labs not only have elucidated how chemotherapy increases cancer risk, but their collaborative work shows promise for preventing metastasis and recurrence of cancer following surgical tumor resection and chemotherapy. “These exciting studies show that pre-operative or peri-chemotherapeutic management of inflammation may stave off cancer recurrences,” Panigrahy said.
“It is always important to realize that the most significant translational science we do in the university is fundamental science,” said Hammock, marveling that “this all began by asking how caterpillars turn into butterflies.”
The research drew major funding from the National Institutes of Health (NIH) through two grants to Hammock, who directs the Superfund Program at UC Davis. He received grants from the National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program; and the NIH RIVER (Revolutionizing Innovative, Visionary Environmental Health Research) Program. The research was also funded by three grants to Panigrahy: Credit Unions Kids at Heart; Joe Andruzzi Foundation; and the C.J. Buckley Pediatric Brain Tumor Fund.
PNAS research article
- Author: Kathy Keatley Garvey
From basic science to applied science.
From studying insects to helping humankind.
The ovarian cancer research published today in the Proceedings for the National Academy of Science (PNAS) can be traced back, in part, to a former graduate student at UC Berkeley trying to answer some basic questions on how a caterpillar becomes a butterfly.
In investigating those basic questions, that graduate student, Bruce Hammock, and fellow graduate student Sarjeet Gill, co-discovered a soluble epoxide hydrolase (sEH). Both scientists are now distinguished professors in the UC system: Hammock, a distinguished professor at UC Davis, and Gill, a distinguished professor at UC Riverside.
For the past 50 years, Hammock has been studying sEH inhibitors, leading to drugs that target such diseases as diabetes, hypertension (heart disease), Alzheimer's disease, and cancer. He recently formed a Davis-based company, EicOsis, to develop an orally active non-addictive drug for inflammatory and neuropathic pain for human beings and companion animals. Human clinical trials are scheduled to begin in 2019. Several seed-fund grants and a NIH/NINDS (National Institute of Neurological Disorders and Stroke) Blueprint Development Grant support EicOsis.
But back to the research published today in PNAS.
Did you know that chemotherapy kills cancer cells, but that the debris of dead and dying cells can lead to inflammation and the surge of more cancerous cells?
The research is the work of a 13-member team from Harvard Medical School/Beth Israel Deaconess Medical Center (BIDMC), UC Davis, Institute of Systems Biology of Seattle, and Emory University School of Medicine of Atlanta. They tested the compound on mice models.
Lead author Allison Gartung of Harvard Medical School/BIDMC described the research as a “novel approach to suppressing therapy-induced tumor growth and recurrence. To prevent tumor-recurrence after therapy, it will be critical to neutralize the inherent tumor-promoting activity of therapy-generated debris,” she said. "Our results indicate that a dual COX-2/sEH inhibitor may offer a novel alternative to protect the body from a debris-mediated inflammatory response.”
Gartung said that the study confirms that chemotherapy-killed ovarian cancer cells “induce surrounding immune cells called macrophages to release a surge of cytokines and lipid mediators that create an optimal environment for tumors to survive and grow.
Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, lamented that “Chemotherapy and surgery, the mainstays of conventional cancer treatment, can act as double-edged swords. It is tragic that the very treatments used to cure cancer are helping it to survive and grow."
Chemist Sung Hee Hwang of the Hammock lab developed the compound, known as PTUPB, for the study. “The dual inhibitor here follows earlier work we did with it, blocking breast and lung tumors in mice,” Hammock said. “PTUPB is already being clinically evaluated for its therapeutic properties in other diseases.” Chemist Jun Yang of the Hammock lab did the mass spectrometry, showing how stabilization of lipid mediators reduces cancer growth and metastasis.
Lead researcher Dipak Panigrahy, a former Harvard physician turned full-time researcher, described chemotherapy and surgery “as our best tools for front-line cancer therapy, but chemotherapy and surgery create cell debris that can stimulate inflammation, angiogenesis, and metastasis. Thus, the very treatment used by oncologists to try to cure cancer is also helping it survive and grow. Overcoming the dilemma of debris-induced tumor progression is critical if we are to prevent tumor recurrence of treatment-resistance tumors which lead to cancer therapy failure.”
The tumor cell debris generates a “cytokine surge” that can result in a perfect storm for cancer progression. “The dual inhibitor acts as a surge protector,” Panigrahy said.
Panigrahy, who led angiogenesis and cancer animal modeling in the laboratory of Judah Folkman, a leading cancer research laboratory, based the debris model on his mother's chemotherapy treatments, and dedicated the research to his mother and “all other women who lost their lives to ovarian cancer.” American Cancer Society statistics show that among women, ovarian cancer ranks fifth in cancer deaths. A woman's risk of ovarian cancer is about 1 in 78; every year more than 14,000 die from the disease.
“Traditional cancer therapy sets up a dilemma,” Panigrahy commented. “Yes, we need to kill cancer cells but the inevitable byproduct of successfully doing so also stimulates tumor regrowth and progression. The more tumor cells you kill, the more inflammation you create, which can inadvertently stimulate the growth of surviving tumor cells. Overcoming the dilemma of debris-induced tumor progression is paramount if we are to prevent tumor recurrence of treatment-resistant tumors – the major reason for failure of cancer therapy. Our studies potentially pave the path for a new strategy for the prevention and treatment of chemotherapy-induced resistance with potential to translate to the clinic. If successful, this approach may also allow us to reduce the toxic activity of current treatment regimens.”
“The collaborative work in this paper not only defines a common problem with current cancer therapy, but it actually offers a potential solution to reduce metastasis and tumor growth following therapy,” said Primo Lara Jr., director of the UC Davis Comprehensive Cancer Center and associate director of Translational Research. “I am pleased that our Center was involved in this exciting project and we hope we can be involved in translating this basic research to the clinic.”
Panigrahy said that non-steroidal anti-inflammatory drugs (NSAIDs), which include aspirin and ibuprofen, reduce pain, fever and inflammation “bit may have severe side effects including stomach and brain bleeding as well as severe cardiovascular and kidney toxicity. They also do not specifically enhance clearing of debris.”
“We are exploring all options to translate PTUPB to cancer patients especially in combination with current cancer therapies such as chemotherapy, radiation, immunotherapy, or surgery which either directly or indirectly may generate tumor cell debris,” Panigrahy said. “Our next step is to investigate whether our findings are consistent with clinical studies involving human cancer.”
Said Hammock: "We have a series of papers largely in PNAS, with the Panigrahy group showing first our soluble epoxide hydrolase inhibitors block tumor growth and metastasis when used with omega3 fish oils or with COX inhibitors and the role for these compounds in regulating a number of mediators of cancer growth."
And to think this all began with a young graduate student at UC Berkeley studying how caterpillars become butterflies.