Novel Therapeutic Pathways in Myelofibrosis: Beyond JAK Inhibition
Panelists discuss how investigational therapies beyond Janus kinase (JAK) inhibition, including epigenetic modulation, telomerase inhibition, PI3K/AKT/mTOR pathway inhibition, immune modulation, TGF-β inhibition, and novel anti-fibrotic agents, are showing promise in improving efficacy and targeting different disease pathways in myelofibrosis.
Summary for Physicians:
Investigational Pathways Showing Promise Beyond JAK Inhibition in Myelofibrosis:
While JAK inhibitors like ruxolitinib remain the backbone of treatment for myelofibrosis (MF), ongoing research is exploring several novel therapeutic strategies that could offer additional options, improve efficacy, or target different disease pathways. These investigational therapies focus on addressing the underlying mechanisms of MF and overcoming limitations seen with current treatments.
1. Epigenetic Modulation (EZH2 Inhibition):
- EZH2 inhibitors (such as tazemetostat) are a promising avenue for MF treatment, especially in patients with mutations in the EZH2 gene. These mutations are known to affect epigenetic regulation, contributing to disease progression and poor prognosis.
- Tazemetostat, which inhibits EZH2, has demonstrated activity in early-phase trials, improving splenomegaly and symptom burden in patients with EZH2 mutations. Ongoing studies are exploring its role in broader MF populations and its combination potential with other agents like JAK inhibitors or chemotherapies.
2. Telomerase Inhibition:
- Telomerase plays a key role in maintaining the stability of chromosome ends, and its dysregulation is implicated in several cancers, including MF.
- Imetelstat, an RNA-based telomerase inhibitor, has shown promise in early trials, especially in patients with high-risk MF. It works by inhibiting telomerase activity, potentially halting disease progression and improving symptoms. Ongoing studies are investigating its effectiveness as a monotherapy and in combination with JAK inhibitors.
3. PI3K/AKT/mTOR Pathway Inhibition:
- Dysregulation of the PI3K/AKT/mTOR pathway is common in MF and contributes to fibrosis and cell survival.
- Selective inhibitors targeting this pathway (eg, copanlisib, buparlisib) are being studied in MF to disrupt abnormal cell signaling, reduce fibrosis, and improve overall disease control. These agents are being evaluated both as monotherapies and in combination with JAK inhibitors.
4. Immune Modulation and Checkpoint Inhibitors:
- Immune checkpoint inhibitors, such as those targeting PD-1 or CTLA-4, are being explored in MF as a way to enhance immune system recognition of malignant cells.
- While these therapies have shown success in other cancers, their role in MF is still under investigation. Trials are focusing on whether these therapies can work synergistically with JAK inhibitors or other agents to overcome immune evasion mechanisms in MF.
5. TGF-β Inhibition:
- TGF-β (Transforming Growth Factor Beta) is a critical mediator of fibrosis in MF and other myeloproliferative neoplasms. Inhibiting TGF-β signaling may help reduce fibrosis and improve clinical outcomes.
- Agents like fresolimumab, an anti–TGF-β antibody, are in clinical trials, aiming to address fibrosis progression and improve splenic size and symptoms in MF patients.
6. Novel Antifibrotic Agents:
Investigational agents targeting fibrosis directly, such as PRM-151 (a recombinant form of human pentraxin-2), aim to reverse or halt fibrotic progression in the bone marrow and spleen. Early trials have shown potential in reducing fibrosis and improving symptom control.
