Our researchers have developed a new strategy to overcome the drug resistance often faced during the treatment of CLL by inhibiting the TNFR family signalling through inhibition of a kinase, PKN1, which is involved in TRAF1 regulation. TRAF1 is overexpressed in 48% of B cell related cancers with highest expression in mature B cell lymphomas and the most refractory B-CLL. Thus targeting TRAF1 in human CLL has the potential to improve the disease outcome. Non-coding single nucleotide polymorphisms in TRAF1 have also been linked to non-Hodgkin’s lymphoma. They have identified PKN1 inhibitors and shown in proof of principal studies that inhibiting PKN1 lowers TRAF1 levels and survival of CLL cells. They have also successfully tested & shown that the PKN1 inhibitors can work in synergy with standard of care drug as further validation for PKN1 as a target in CLL.
Chronic lymphocytic Leukemia (CLL) is the most common human leukemia with 20,720 new cases and 3930 deaths expected in the US in 2019 (www.cancer.org). CLL is considered to be largely a disease of the lymph node and bone marrow, where B-CLL cells receive survival signals, including tonic signals through their antigen specific B cell receptor (BCR). Several promising new therapies for CLL target BCR signaling or cell survival, including the phosphatidyl inositol-3-kinase inhibitor idelalisib, the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, as well as the Bcl-2 antagonist venetoclax. While these treatments are showing great promise, responses are not always durable and when relapse occurs there are limited treatment options available.
- PKN1 identified as a new target for inhibition in CLL
- First generation PKN1 inhibitor, along with a companion biomarker identified
- Proof of Principle combination therapy with standard of care cancer drug studies show enhanced cell death
IP - Provisional patent application filed May 2019