SIL204 reduces tumors, slows spread in pancreatic cancer models
Therapy is designed to target KRAS gene mutations
Administering Silexion Therapeutics‘ investigational therapy SIL204 under the skin effectively reduced the growth of primary tumors and their metastatic spread to various organs in mouse models of pancreatic cancer.
“These results mark the first time we’ve demonstrated SIL204’s ability to address metastatic disease through subcutaneous [under-the-skin] administration,” Ilan Hadar, Silexion’s chairman and CEO, said in a company press release. “The ability to deliver our therapy systemically [bodywide] and still effectively target both primary pancreatic tumors and their metastases represents a significant potential advantage for treating this devastating disease.”
More than 90% of cases of pancreatic adenocarcinoma, the most common form of pancreatic cancer, are associated with mutations in the KRAS gene, which encodes an enzyme of the same name that acts like an on-and-off switch to control cell growth and survival.
When KRAS is mutated, the switch stays on, cells grow out of control, and cancer develops. Two KRAS mutations in particular — G12D and G12V — account for more than 75% of pancreatic adenocarcinoma cases.
What is SIL204?
SIL204 is a small interference RNA (siRNA) molecule designed to specifically bind to the messenger RNA, or mRNA, of a KRAS gene with G12D or G12V mutations, promoting its destruction. mRNA is the intermediate molecule derived from DNA that guides protein production.
By triggering the destruction of mutated KRAS’s mRNA, the therapy should prevent the production of the always-active KRAS enzyme, thereby slowing tumor growth and spread. SIL204, administered subcutaneously or directly into the tumor, is meant to be used as an adjunct to standard-of-care chemotherapy.
SIL204 is an optimized version of Loder, the company’s first-generation G12D/G12V-targeting siRNA product that generated promising results in a Phase 2 clinical trial (NCT01676259) involving people with KRAS-driven inoperable pancreatic cancer.
Specifically, for patients with G12D or G12V mutations, Loder plus chemotherapy extended their overall survival by a median of more than nine months over chemotherapy alone, a difference that nearly reached statistical significance.
New SIL204 data
The new data concerned preclinical experiments of SIL204, delivered through subcutaneous injection, in ortotopic xenograft models of pancreatic cancer related to G12D mutations.
Orthotopic xenograft models involve implanting human cancer cells into mice in the same organ or tissue from which the cancer originated in the patient. This allows the cancer’s development to be assessed and potential treatments evaluated in a clinically relevant environment that mimics the disease process in people.
In the mouse model with human pancreatic cancer cells carrying the G12D mutation in both copies of the KRAS gene, subcutaneous SIL204 treatment reduced the number of cancer cells by about 70% after about a month compared with untreated mice.
In the model with cells carrying the G12D mutation in only one KRAS gene copy (Panc-1 moodel), the treatment was associated with a dose-dependent reduction in cancer cells. The highest dose led to a 12% drop in cancer cell numbers compared with a more than 100% increase in untreated mice. This difference was statistically significant.
SIL204 also reduced the number of cancer cells by 80% in a model with human pancreatic cancer cells without a KRAS mutation, according to the company.
When the researchers looked at other organs of the Panc-1 model and in the model without KRAS mutations, they found that SIL204 treatment substantially slowed cancer spread to the liver, intestine, spleen, and stomach.
“These orthotopic model results represent a pivotal advancement in our development program,” said Mitchell Shirvan, PhD, chief scientific officer of Silexion. “While our previous data showed SIL204’s ability to reduce tumor growth in standard models, these new findings provide initial validation of its potential effectiveness in a much more clinically relevant setting. Particularly exciting is the demonstration that SIL204 can significantly reduce metastatic spread when administered subcutaneously, suggesting potential for treating both primary and metastatic disease with a minimally invasive delivery method.”
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