Research Terms
This STAT3-induced 11-gene signature can predict which cancers will respond to synthetic lethal therapies, such as poly ADP-ribose polymerase (PARP) inhibitors that have been successfully used in ovarian and breast cancer. According to the International Agency for Research on Cancer, the global cancer burden in 2020 alone included 19.3 million new cancer cases and nearly 10 million cancer deaths. PARP inhibitors have proven effective in treatments of breast and ovarian cancer arising from a mutation in BRCA genes. Studies indicate that many patients have cancers that respond to PARP inhibitor therapy despite lacking mutations in BRCA genes. However, predicting and therefore identifying patients with cancers that will respond to PARP inhibitors is a major challenge.
Researchers at the University of Florida have discovered the vital role of a known oncogene, STAT3, in inhibiting homologous recombination (HR) repair of DNA, a major mechanism that cancer cells need in order to proliferate. Cancers with BRCA gene mutations also lack HR repair, making them susceptible to PARP inhibitors. The new linkage of STAT3 to HR impairment is a finding that forecasts that many more cancers, beyond breast and ovarian cancers, are likely to be susceptible to PARP inhibitors and synthetic lethal therapies. Thus, the discovery expands the range of cancers that could be treated with synthetic lethal therapies. In addition to this, researchers have identified a STAT3 induced 11-gene signature that can predict which cancers are likely to respond to therapy with PARP inhibitors.
An assay that can determine if synthetic-lethal therapies, such as by PARP inhibitors, will kill a patient’s cancer cells
Cancer cells depend on molecular mechanisms to repair DNA to proliferate. If one mechanism is lost, the cell relies on the remaining mechanisms of DNA repair. Proteins encoded by BRCA genes are critical for homologous recombination (HR) repair, a major type of DNA repair for cancer cells. In breast and ovarian cancers that carry mutations in BRCA1 or BRCA2 genes, HR repair is defective. Synthetic lethal therapies inhibit PARP, an enzyme important for another type of DNA repair, killing the cancer. However, while only 5 to 10 percent of breast and ovarian cancers have a BRCA gene mutation, many more breast, ovarian, and other cancers are susceptible to PARP inhibition, which suggests that something other than the mutation inhibits HR repair. UF researchers have found that a prominent oncogene known to be overactive in two-thirds of human cancers, Signal Transducer and Activator of Transcription 3 (STAT3), inhibits HR repair. In addition, researchers have identified an 11-gene signature downstream of STAT3 that can predict which cancers are likely to respond to therapy with PARP inhibitors. This small gene signature can be developed into a real-time PCR/chip/microarray-based clinical test.
This approach prevents EBV-associated malignancies by inhibiting the Epstein-Barr virus (EBV) lytic phase malignancies. EBV is a ubiquitous oncogenic herpesvirus, causing an estimated 300,000 new cancers and 200,000 deaths each year. EBV commonly causes infectious mononucleosis in adolescents but also contributes to multiple sclerosis, and drives several life-threatening malignancies, including post-transplant lymphoproliferative disorder (PTLD), lymphomas, nasopharyngeal cell carcinoma, and gastric cancer. Like all herpesviruses, EBV has both latent/dormant and lytic phases. In the host B cell, EBV is primarily in its latent state, from which such malignancies can arise. In the setting of immunosuppression, such as after organ transplantation, infection by donor-derived EBV or lytically reactivated EBV not only dysregulates host gene expression but also spreads the infection to new B cells, ultimately leading to the development of PTLD and lymphoma. EBV-specific vaccines or antivirals have yet to be developed, and conventional management of PTLD relies on frequent EBV load monitoring and reactive treatment with broad B cell-depleting drugs like rituximab. These approaches are limited by delayed intervention, indiscriminate immune suppression, and increased vulnerability to infection and long-term immunodeficiency.
Studies have revealed the lytic cycle of EBV is triggered by activation of the host cell inflammasome either by cell stress, damage, or activation of surface IgG, also known as the B cell receptor. With the inflammasome and B cell receptor signaling linked, researchers at the University of Florida have discovered EBV reactivation is preventable by using inhibitors of the Bruton’s tyrosine kinase (BTK) – a key enzyme in signaling between the B cell receptor and the inflammasome. BTK inhibitor therapy provides a targeted, early, and sustained method to blocking EBV reactivation, thereby protecting against EBV-associated malignancies without compromising overall immune function. With an adaptive dosing regime, BTK therapy can also be adjusted based on patient risk and clinical context.
BTK inhibitors to prevent EBV reactivation and reduce the incidence of EBV-driven lymphoproliferative diseases
This advanced EBV reactivation prevention system uses Bruton's Tyrosine Kinase (BTK) inhibitors to precisely block the viral switch from latency to lytic phase in B cells. BTK is a critical enzyme in B cell receptor signaling and inflammasome activation, both are pathways exploited by EBV to initiate viral replication and drive lymphoproliferative disease. The technology features both irreversible and reversible BTK inhibitor compounds, disrupting BTK-mediated phosphorylation events and downstream signaling cascades. This interruption prevents the activation of the EBV lytic cycle, showcased by reduced expression of key viral proteins (ZEBRA and EA-D) and decreased cleavage of procaspase 1, a marker of inflammasome activation and programmed cell death. By inhibiting BTK, the system prevents EBV-driven activation and proliferation of EBV-cancer cells with high specificity. This technology’s ability to target the molecular machinery required for EBV reactivation makes it an invaluable tool for precise prevention of EBV-driven malignancies while preserving healthy immune function, avoiding indiscriminate B cell destruction that is often used to prevent EBV-cancers.
This dual targeting agent reactivates the Epstein-Barr virus (EBV) to treat cancer patients by targeting enzymes that support the EBV latent state and thereby, uncontrolled EBV-cancer cell growth. The Epstein-Barr virus is a human herpesvirus infecting most humans. It is one of the two members of the gamma-herpesvirus family known to cause cancer in humans, infecting B cells of the immune system and epithelial cells. Once EBV’s initial lytic infection is brought under control, EBV latency persists in the individual’s B cells for the rest of their life. Most people become infected with EBV and gain adaptive immunity. In the United States, about half of all five-year-old children and about 90% of adults have evidence of previous infection.
EBV is associated with various non-malignant, premalignant, and malignant lymphoproliferative diseases, such as Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, post-transplant lymphoproliferative disease/lymphoma, nasopharyngeal cell carcinoma, and gastric carcinoma. Lymphomas are among the most common blood cancers in the United States, with over 80,000 new cases of Hodgkin’s and Non-Hodgkin’s lymphoma diagnosed annually. Oncolytic therapies destroy cancer cells by purposefully reactivating the lytic phase of EBV resulting in cancer cell death directly and indirectly through the genomic incorporation of an antiviral. Molecules that induce the lytic phase of EBV include DNA methyltransferase inhibitor, immunoglobulins, and HDAC inhibitors. Current therapies rely heavily on pan-HDAC inhibitors, which non-selectively block many enzymes, leading to significant toxicity, resistance, and limited long-term efficacy.
Researchers at the University of Florida have developed a dual targeting agent to selectively degrade HDAC3 and HDAC8-- enzymes directly linked to the viral latent state and therefore lymphoma progression. By guiding these enzymes to the cell’s natural recycling system for complete removal, the targeting agent delivers deeper, selective, and longer-lasting therapeutic effects with the potential for fewer side effects and improved patient outcomes.
Targets enzymes, HDAC3 and HDAC8, to reactivate the Epstein-Barr virus in cancer cells for targeted and improved treatment
This oncolytic dual-targeting agent is a next-generation protein degrader targeting HDAC3 and HDAC8. These enzymes help control and determine the genes expressed and active in cancer. Instead of simply blocking enzyme activity for a short time, the targeting agent guides HDAC3 and HDAC8 to the cell’s natural recycling system and tags them for removal. Rather than blocking the enzyme, it deletes it completely. By clearing the proteins from the cell, it delivers deeper and longer-lasting control with the potential for fewer off-target effects and less resistance.
