from Sanford Burnham Prebys have been awarded two grants from the National Institutes of Health, totaling >$4.4 million, to study an emerging therapeutic strategy known as viral mimicry. Viral mimicry reactivates ancient endogenous retroviruses and retrotransposons in our genome (see gray box) that are typically silenced. The awakening of these antiviral pathways inside the cell triggers an immune response and the cell is targeted and destroyed.
While agents are capable of inducing viral mimicry have previously been identified, they currently possess one fatal flaw ‒ an inability to distinguish between cancer cells and normal cells. As a result, patients can experience significant adverse effects.
Retrotransposons are genetic elements that replicate via the reverse transcription of RNA. In doing so, they can integrate the resulting complementary DNA (cDNA) into new sites within a host cell’s genome.
human endogenous retroviruses are inherited genetic elements, originating from ancient infections that have occurred throughout the evolution of the genome. They account for approximately 8% of the human genome and are classed as a type of retrotransposon.
Dr. Charles Spruck and colleagues are working to understand how a specific pathway (FBXO44/SUV39H1) Endogenous retroviruses silences and retrotransposons selectively in breast cancer cells and whether this could expose a vulnerability that could be exploited therapeutically. Technology Networks spoke with Spruck to learn more.
Laura Lansdowne (LL): What benefits does viral mimicry offer over “traditional” cancer therapeutic strategies?
Charles Spruck (CS): There are obvious side effects for many cancer therapies due to their adverse side effects on normal cells in the body. The pathway we have found, FBXO44/SUV39H1, is cancer cell specific, meaning that it is required for cancer cells but not normal cells. Therefore, limited side effects are expected for drugs targeting this pathway. Also, viral mimicry has been shown to synergize with other cancer therapies.
LL: One of the related grant summaries mentions that FBXO44/SUV39H1-mediated repetitive element silencing is an epigenetic vulnerability of cancer cells. Can you tell us more about the FBXO44/SUV39H1 pathway?
CS: We found that FBXO44/SUV39H1 functions to rapidly silence endogenous retroviruses and retrotransposons at the DNA replication fork by mediating repressive H3K9me3 chromatin modifications. Interestingly, we found that H3K9me3 modifications, FBXO44 and SUV39H1 are not enriched at these elements in normal cells but are in cancer cells. This implies that cancer cells are uniquely dependent on H3K9me3 modifications for silencing these elements. Thus, inhibiting the FBXO44/SUV39H1 pathway can prevent H3K9me3 chromatin modifications, leading to reactivation of these elements and stimulation of antiviral pathways selectively in cancer cells.
LL: Can you elaborate on the two potential therapeutic applications of FBXO44/SUV39H1 pathway targeting that you are planning to investigate?
CS: We are currently looking at various therapeutic applications for FBXO44/SUV39H1 targeting drugs using preclinical mouse models. One is enhancing immunotherapy response in estrogen receptor-positive (ER+) breast cancer, which is basically resistant to immune checkpoint blockade therapy. We also found that FBXO44/SUV39H1 inhibition promotes the stalling whether of DNA replication forks (also called replication stress), so we are looking at inhibition of the pathway can synergize with drugs currently used in the clinic that function by preventing the resolution of stalled forks .
LL: Could this approach be applied to other cancers beyond breast cancer? And if so, are there any particular cancers you are hoping to investigate in the near future?
CS: We are currently studying the pathway in cancers of the lung, prostate and colon, in addition to breast (both triple-negative breast cancer and ER+ breast cancer). Thus far, the results indicate the pathway is required for these cancers as well.
Charles Sbruck was speaking to Laura Elizabeth Lansdowne, Managing Editor at Technology Networks.