SHP-1 Activation by Sorafenib Derivatives as a Novel Therapeutic Strategy for Mantle Cell Lymphoma

Mantle Cell Lymphoma (MCL) is a rare yet aggressive form of blood cancer that arises from B lymphocytes. Although most patients initially respond to chemotherapy and immune-based treatments, the disease often comes back, and long-term cures remain uncommon. The introduction of medicines known as BTK inhibitors has improved survival for many people, but nearly all patients eventually experience disease progression. Those whose cancer carries changes in a key gene called TP53 respond especially poorly and face limited treatment options, making this one of the most urgent unmet needs in lymphoma care. Our recent research has uncovered a key mechanism that helps explain why TP53-altered MCL resists therapy. The TP53 gene normally supports a natural “braking system” within cancer cells through a protein called SHP1, which helps regulate cell growth and signaling. When TP53 is damaged or missing, SHP1 expression is reduced, leaving the cancer cells without this internal brake. As a result, even when BTK inhibitors block a major growth pathway, the tumor cells can reactivate it and continue to survive. This finding suggests that restoring SHP1 activity could enhance the effects of BTK inhibitors and help overcome treatment resistance. Encouragingly, several existing medicines, including sorafenib and closely related compounds developed for other cancers, can activate SHP1 and restore its tumor-suppressive function. Our early laboratory work shows that these SHP1-activating drugs not only kill MCL cells directly but also influence the tumor’s immune environment. They can reprogram immune cells called macrophages, which normally help tumors grow, into a more active state that attacks the cancer instead. This dual function—directly suppressing cancer cells and stimulating immune defenses—makes SHP1 activation a uniquely promising strategy. In this project, we will first test combinations of SHP1-activating medicines with BTK inhibition in advanced MCL mouse models to determine how effectively they work together and how they remodel the tumor environment. We will then examine how these medicines influence macrophages and other immune cells to strengthen anti-tumor responses. Finally, we will conduct an early clinical study to evaluate the safety and potential benefit of combining regorafenib, an SHP1-activating drug, with BTK inhibition in patients with relapsed MCL, followed by a focused expansion in patients whose disease carries TP53 changes. By linking laboratory, immune, and clinical research, this study aims to establish a new, more durable treatment strategy that could greatly improve outcomes for patients with aggressive, treatment-resistant MCL and provide insights applicable to other blood cancers.