Navigation Links
Penn vet researchers show lymphoma drug shrinks dog tumors, could lead to human treatment
Date:7/15/2011

PHILADELPHIA There are many kinds of cancers of the immune system, but one, Activated B-Cell Diffuse Large B-Cell Lymphoma, or ABC-DLBCL, is particularly common and pernicious. Researchers at the University of Pennsylvania's School of Veterinary Medicine have shown for the first time that dogs that develop this disease spontaneously share the same aberrant activation of a critical intracellular pathway with humans. They also found that a drug designed to disrupt this pathway helps to kill tumor cells in the dogs' cancerous lymph nodes.

The research was conducted by Nicola Mason, assistant professor of medicine at Penn Veterinary, along with Michael J. May, associate professor of pharmacology; postdoctoral fellow Anita Gaurnier-Hausser; and veterinary clinical pathologist Reema Patel.

Their work was published in the journal Clinical Cancer Research.

B-cells are the part of the immune system that produce antibodies and protect the body against invading microorganisms or allergens. In ABC-DLBCL, the intracellular signaling pathway involved in B-cell activation and proliferation is, as the name of the disease suggests, constantly activated.

"This signaling pathway, called NF-kappaB, is critical in immune function; following an encounter with antigen, lymphocytes need to be activated and proliferate so that there are sufficient numbers to deal with the invading organism," Mason said. "But in humans with ABC-DLBCL, and also in dogs with spontaneous DLBCL, this pathway is constitutively active and drives lymphocytes to proliferate continuously."

Moreover, these malignant B-cells are resistant to apoptosis, or cell death. Their unchecked growth is the basis of the lymph node tumors that are a hallmark of the disease.

For many years, researchers have been investigating ways of interrupting the malfunctioning pathway that forms the tumors and provides resistance to chemotherapy-induced cell death. In order to test whether a canine model for inhibitors would have relevance to cancer treatment in humans, the Penn team first showed that the same aberrant activation of the NF-kappaB pathway exists in dogs.

They then went on to demonstrate that inhibition of this pathway using a drug known as NEMO Binding Domain, or NBD, peptide led to increased cell death of malignant lymphocytes in a laboratory setting. The next step was to determine whether this peptide could similarly inhibit NF-kappaB activity when used directly in the dogs with the disease.

Treatment of DLBCL in dogs is similar to humans; the cancer usually responds well to chemotherapy, but patients frequently relapse with drug-resistant disease. The five-year survival prognosis for humans is about 50 percent, but in dogs the survival rate is much worse, with more 85 percent of dogs relapsing within the first year and the majority succumbing to their disease during the first or second round of chemotherapy.

Having determined the presence of aberrant pathway activity in the dogs with spontaneous DLBCL and that inhibition of this pathway can lead to increased cell death, the researchers performed a small pilot trial to determine the efficacy of the NBD peptide in dogs that had relapsed with drug resistant lymphoma.

The results were encouraging.

"We injected one malignant lymph node with the NBD peptide and followed up with chemotherapy. One week after a single dose of peptide, the lymph node we injected was a lot smaller than the other cancerous lymph nodes," Mason said. "This suggests that the peptide either acts alone or synergistically with the chemotherapy drugs to kill the tumor cells."

Testing the peptide in a live animal model, rather than in tumor cells taken from cell lines in a Petri dish, accelerates the prospects of this research leading to clinical treatments for both dogs and humans.

"The identification of a comparable molecular pathogenesis of ABC-DLBCL between dogs and humans, coupled with our ability to investigate the therapeutic benefit of targeting this aberrant NF-kappaB pathway in a clinically relevant, large animal model is a perfect example of the 'bench to bedside' paradigm of translational medicine," Mason said. "It's been over 10 years since this pathway was recognized in ABC-DLBCL in humans; however, this is the first indication that specific inhibition of this pathway may have a beneficial effect in human and canine patients with this disease."

Mason and her colleagues are now testing whether the peptide is systemically effective when introduced intravenously, rather than directly injected into a single tumor. The drug has shown to have minimal side effects on the immune systems of small animals, and a successful and safe trial in dogs could not only pave the way to a novel approach to the treatment of this disease in pet dogs but also could lead to clinical trials in humans with this type of lymphoma.


'/>"/>

Contact: Evan Lerner
elerner@upenn.edu
215-573-6604
University of Pennsylvania
Source:Eurekalert

Related biology news :

1. Wood products part of winning carbon-emissions equation, researchers say
2. IRCM researchers uncover a new piece of the puzzle in the development of our nervous system
3. TUM researchers discover a new switch in resistance to plant diseases
4. BUSM researchers urge awareness of dietary iodine intake in postpartum Korean-American women
5. Researchers study pesticide pathways into the atmosphere
6. Johns Hopkins researchers identify new genetic risk factor for sudden cardiac death
7. Johns Hopkins researchers awarded $32 million
8. U of T researchers build an antenna for light
9. Researchers closing in on safe treatment for parasitic diseases
10. Unnatural chemical allows Salk researchers to watch protein action in brain cells
11. UTMB-led researchers awarded $7.8 million for Gulf spill study
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:5/16/2016)... --  EyeLock LLC , a market leader of iris-based ... IoT Center of Excellence in Austin, Texas ... embedded iris biometric applications. EyeLock,s iris authentication ... with unmatched biometric accuracy, making it the most proven ... platform uses video technology to deliver a fast and ...
(Date:4/28/2016)... India , April 28, 2016 ... Infosys (NYSE: INFY ), and Samsung SDS, a ... that will provide end customers with a more secure, ... services.      (Logo: http://photos.prnewswire.com/prnh/20130122/589162 ) , ... services, but it also plays a fundamental part in enabling ...
(Date:4/19/2016)... The new GEZE SecuLogic access ... "all-in-one" system solution for all door components. It can ... door interface with integration authorization management system, and thus ... minimal dimensions of the access control and the optimum ... offer considerable freedom of design with regard to the ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... 2016 Houston Methodist Willowbrook Hospital has ... Association to serve as their official health care ... Willowbrook will provide sponsorship support, athletic training services, ... coaches, volunteers, athletes and families. "We ... Association and to bring Houston Methodist quality services ...
(Date:6/23/2016)... , June, 23, 2016  The Biodesign Challenge ... envision new ways to harness living systems and biotechnology, ... Art (MoMA) in New York City ... 130 participating students, showcased projects at MoMA,s Celeste Bartos ... Paola Antonelli , MoMA,s senior curator of architecture and ...
(Date:6/23/2016)... (PRWEB) , ... June 23, 2016 , ... STACS DNA ... Technical Leader at the Arkansas State Crime Laboratory, has joined STACS DNA as a ... STACS DNA team,” said Jocelyn Tremblay, President and COO of STACS DNA. “In further ...
(Date:6/23/2016)... 2016  Blueprint Bio, a company dedicated to identifying, ... community, has closed its Series A funding round, according ... "We have received a commitment from Forentis Fund ... to meet our current goals," stated Matthew Nunez ... to complete validation on the current projects in our ...
Breaking Biology Technology: