October 25, 2011 (San Francisco, California) — Laboratory studies conducted at the Memorial Sloan-Kettering Cancer Center in New York City suggest that triple-negative breast cancer (TNBC) might respond to treatment with an oncolytic agent.
The findings were reported here at the American College of Surgeons 97th Annual Clinical Congress.
"We found that [the mutant herpes virus] NV1066 is an effective oncolytic agent against triple-negative breast cancer in vitro and in vivo," said Sepideh Gholami, MD, a research fellow in the laboratory of Yuman Fong, MD, which is considered to be at the forefront in oncolytic viral therapy research.
"Oncolytic viruses are attractive therapeutic agents that destroy tumor cells without the accompanying destruction of normal cells," she said. The mitogen-activated protein kinase (MAPK) signaling pathway is known to be important in TNBC, and activated (phosphorylated) MAPK signaling has been shown to mediate efficient replication of NV1066 through the deletion of the delta gamma(1)34.5 gene.
In other words, she said, TNBC cells have high levels of phosphorylated MAPK, a protein that promotes tumor growth and contributes to resistance to current therapies. The herpes virus specifically targets cells that overexpress this protein, which is the rationale for this approach.
The study aimed to determine whether NV1066 could kill TNBC cells effectively. The researchers also examined the functional effects of NV1066 on the MAPK signal transduction pathway during viral infection.
Dr. Gholami and colleagues infected 5 different TNBC cell lines with the NV1066 herpes simplex virus. After treatment with the virus, the most sensitive cell lines demonstrated a 90% cell kill rate within 1 week; the less sensitive lines demonstrated a 70% cell kill rate.
In addition, sensitive cell lines expressed higher baseline levels of phosphorylated MAPK than resistant cell lines, and viral infection caused the downregulation of phosphorylated MAPK by 48 hours, she reported.
"TNBC cells support efficient viral replication, with over 1 million copy numbers observed, which is more than a 1000-fold increase," she said.
"Since baseline phosphorylated MAPK levels positively correlated with sensitivity to NV1066, they might therefore be used as a clinical marker for selecting patients for viral therapy," she suggested.
Tumor Regression Almost Complete
The researchers created flank tumors and injected them with NV1066 or a control compound. Within 5 days, tumor volume significantly decreased in the experimental group; within 3 weeks, they observed "near-complete tumor regression," Dr. Gholami reported.
While tumors in control animals grew from a mean of 200 to 700 cm3, they essentially disappeared in animals infected with the oncolytic herpes virus (P < .002). The mean volume of treated tumors was reduced 42-fold, compared with those treated with the control compound (P = .0001), by day 19.
"The difference was dramatic because sometimes we can stop tumor growth but not necessarily achieve tumor regression," she explained. "Our results are very exciting because we may be coming up with an approach that could potentially exploit the unique vulnerabilities of these specific cancer cells."
Oncolytic viruses are being studied in head and neck cancers, but this study is the first to show promise in TNBC. If additional animal studies are also positive, human clinical trials are expected.
"Our goal is to improve this version of the virus and get it into a clinical trial," Dr. Gholami said. She added that NV1066 might also have a role as a sensitizer to radiation therapy and to treatment with agents targeting the epidermal growth-factor receptor, by virtue of its ability to downregulate MAPK.
Ryan Fields, MD, from Washington University in St. Louis, Missouri, finds the results interesting, and suggested that a better understanding of viral biology will help move this potentially therapeutic field forward. "Gene therapy has been around a long time using a number of different viral agents, and success has often been limited by a lack of understanding of the viral biology," he said.
He questioned whether the use of an oncolytic virus might be producing an immune response, because "you are generating a large amount of tumor necrosis when you inject the virus directly into the tumor," he said. He also noted that "this seems to be a nice strategy to use in combination with a MEK inhibitor."
Dr. Gholami indicated that her group is, indeed, studying the agent in combination with a MEK inhibitor and an mTOR inhibitor, "with very promising results."
Dr. Gholami and Dr. Fields have disclosed no relevant financial relationships.
American College of Surgeons (ACS) 97th Annual Clinical Congress. Presented October 24, 2011.
The findings were reported here at the American College of Surgeons 97th Annual Clinical Congress.
"We found that [the mutant herpes virus] NV1066 is an effective oncolytic agent against triple-negative breast cancer in vitro and in vivo," said Sepideh Gholami, MD, a research fellow in the laboratory of Yuman Fong, MD, which is considered to be at the forefront in oncolytic viral therapy research.
"Oncolytic viruses are attractive therapeutic agents that destroy tumor cells without the accompanying destruction of normal cells," she said. The mitogen-activated protein kinase (MAPK) signaling pathway is known to be important in TNBC, and activated (phosphorylated) MAPK signaling has been shown to mediate efficient replication of NV1066 through the deletion of the delta gamma(1)34.5 gene.
In other words, she said, TNBC cells have high levels of phosphorylated MAPK, a protein that promotes tumor growth and contributes to resistance to current therapies. The herpes virus specifically targets cells that overexpress this protein, which is the rationale for this approach.
The study aimed to determine whether NV1066 could kill TNBC cells effectively. The researchers also examined the functional effects of NV1066 on the MAPK signal transduction pathway during viral infection.
Dr. Gholami and colleagues infected 5 different TNBC cell lines with the NV1066 herpes simplex virus. After treatment with the virus, the most sensitive cell lines demonstrated a 90% cell kill rate within 1 week; the less sensitive lines demonstrated a 70% cell kill rate.
In addition, sensitive cell lines expressed higher baseline levels of phosphorylated MAPK than resistant cell lines, and viral infection caused the downregulation of phosphorylated MAPK by 48 hours, she reported.
"TNBC cells support efficient viral replication, with over 1 million copy numbers observed, which is more than a 1000-fold increase," she said.
"Since baseline phosphorylated MAPK levels positively correlated with sensitivity to NV1066, they might therefore be used as a clinical marker for selecting patients for viral therapy," she suggested.
Tumor Regression Almost Complete
The researchers created flank tumors and injected them with NV1066 or a control compound. Within 5 days, tumor volume significantly decreased in the experimental group; within 3 weeks, they observed "near-complete tumor regression," Dr. Gholami reported.
While tumors in control animals grew from a mean of 200 to 700 cm3, they essentially disappeared in animals infected with the oncolytic herpes virus (P < .002). The mean volume of treated tumors was reduced 42-fold, compared with those treated with the control compound (P = .0001), by day 19.
"The difference was dramatic because sometimes we can stop tumor growth but not necessarily achieve tumor regression," she explained. "Our results are very exciting because we may be coming up with an approach that could potentially exploit the unique vulnerabilities of these specific cancer cells."
Oncolytic viruses are being studied in head and neck cancers, but this study is the first to show promise in TNBC. If additional animal studies are also positive, human clinical trials are expected.
"Our goal is to improve this version of the virus and get it into a clinical trial," Dr. Gholami said. She added that NV1066 might also have a role as a sensitizer to radiation therapy and to treatment with agents targeting the epidermal growth-factor receptor, by virtue of its ability to downregulate MAPK.
Ryan Fields, MD, from Washington University in St. Louis, Missouri, finds the results interesting, and suggested that a better understanding of viral biology will help move this potentially therapeutic field forward. "Gene therapy has been around a long time using a number of different viral agents, and success has often been limited by a lack of understanding of the viral biology," he said.
He questioned whether the use of an oncolytic virus might be producing an immune response, because "you are generating a large amount of tumor necrosis when you inject the virus directly into the tumor," he said. He also noted that "this seems to be a nice strategy to use in combination with a MEK inhibitor."
Dr. Gholami indicated that her group is, indeed, studying the agent in combination with a MEK inhibitor and an mTOR inhibitor, "with very promising results."
Dr. Gholami and Dr. Fields have disclosed no relevant financial relationships.
American College of Surgeons (ACS) 97th Annual Clinical Congress. Presented October 24, 2011.
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