Nav: Home

Innovative therapy strategy for pancreatic cancer uses engineered exosomes targeting mutated KRAS gene

June 07, 2017

HOUSTON - Genetic manipulation of exosomes, virus-sized particles released by all cells, may offer a new therapeutic approach to treating pancreatic cancer, according to a study at The University of Texas MD Anderson Cancer Center.

Findings from the study, led by Valerie LeBleu, Ph.D., assistant professor of Cancer Biology, and Sushrut Kamerkar, Ph.D., assistant student in the MD Anderson UT Health Graduate School of Biomedical Sciences and the Cancer Biology Program, were published in the June 7 online issue of Nature.

Earlier MD Anderson investigations demonstrated exosomes as a factor in detecting pancreatic cancer, but these latest findings reveal genetically altered exosomes as a potentially novel approach for direct and specific targeting of mutated KRAS, the cancer gene commonly linked to pancreatic cancer.

In the study, exosomes, which are generated by all cells and are naturally present in blood, were modified as "iExosomes," capable of delivering small RNA to specifically target mutant KRAS, resulting in disease suppression and increased overall survival in mouse models. The investigators utilized a targeting method called RNA interference (RNAi) which, when delivered via these natural nanoparticles or exosomes, zero in on mutant KRAS in pancreas cancer cells, impacting tumor burden and survival in multiple pancreas cancer models. The team showed that exosomes could serve as an efficient carrier of RNAi, given that these nano-sized vesicles easily travel across the body and enter cells, including cancer cells.

When mutated, KRAS acts as a molecular on-off switch that gets stuck in an "on" position. It is mutated in 80 to 95 percent of pancreatic ductal adenocarcinomas (PDAC), the most frequent mutation in this cancer. The study demonstrated that iExosomes were able to deliver KRAS-specific targeting genetic material called siRNA and shRNA, and were more efficient than their synthetic counterpart, iLiposomes, which do not present with the natural complexities and advantages that exosomes display.

"Our studies suggest that exosomes exhibit a superior ability to deliver siRNA molecules and suppress aggressive pancreatic tumor growth when compared to liposomes," said LeBleu. "We also demonstrated that the presence of CD47 on exosomes' allows for evasion from phagocytosis by the circulating monocytes."

CD47 is a protein involved in many cellular processes, including cell death, growth and migration. Phagocytosis is a process by which white blood cells called macrophages digest cellular debris and foreign bodies and particles. Monocytes are the largest kind of white blood cell important to the immune system.

"CD47 basically initiates a 'don't eat me' signal that inhibits phagocytosis," said Kamerkar. "We identified how CD47 contributes to suppressing exosomes clearance from circulation, and enhancing their delivery to pancreatic cancer cells."

Despite current standard of care, the prognosis for patients with PDAC is poor and effective new therapies are needed. PDAC genetic analyses show that KRAS mutations are encountered in a majority of patients and play a significant role in cancer initiation, progression and metastasis. Dampening oncogenic KRAS using genetic manipulation in mice inhibited tumor progression despite the presence of other genetic defects. Until this study, a direct and specific targeting of KRAS has been elusive.

The team also showed that the cellular process macropinocytosis, which participates in cell scavenging nutrients and vesicles, contributes to exosomes uptake in cancer cells with mutant KRAS.

"The increased number of exosomes reaching the pancreas may gain further advantage to enter KRAS-associated cancer cells as a result of enhanced macropinocytosis, which concurs with previous findings," said Kamerkar. "Our results also support an efficient uptake of iExosomes despite the dense stroma in pancreatic tumors. Further study is needed to gain a better understanding about whether exosomes entering cells via macropinocytosis have other features that could enhance their anti-tumor capabilities."
-end-
MD Anderson research team members included Hikaru Sugimoto, M.D., Ph.D., Sujuan Yang, and Raghu Kalluri, M.D., Ph.D., all of Cancer Biology; and J. Jack Lee, Ph.D., Biostatistics. Also participating was Sonia Melo, Ph.D., the Universidade do Porto, Porto, Portugal. The study was funded by the Cancer Prevention and Research Institute of Texas and the Knowledge Gap funding of MD Anderson; the Khalifa Bin Zayed Al Nahyan Foundation; and the National Institutes of Health (CA16672 and 5U24-CA126577).

Disclosures: MD Anderson and Kalluri hold patents in the area of exosome biology and are licensed to Codiak Biosciences, Inc., for which both are stock equity holders. Kalluri receives research support from Codiak and is a member of its board of directors, while LeBleu served for one day in 2016 as a paid Codiak consultant.

University of Texas M. D. Anderson Cancer Center

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...