Dr. Tessier is a clinician-scientist in training at Mayo Clinic with a career goal of leading research focused on high risk blood cancers, particularly myeloid neoplasms (MN) and leukemia. These cancers often carry genetic changes that make them resistant to treatment.
Among the most aggressive and challenging of these are MN with mutations in the TP53 gene (TP53mut), which are associated with rapid disease progression, resistance to all available leukemia therapies, and extremely poor survival. TP53mut MN account for up to 40% of therapy-related MN, a devastating scenario in which patients who have already endured one cancer and its treatment subsequently develop a second, treatment-related malignancy of the blood. Aggressive cancers like TP53mut MN lead to frequent hospitalizations, infections, fatigue, inability to work or live independently, and psychosocial distress. These patients need intensive, ongoing care that involves specialized expertise, often requiring multiple cycles of various therapies. Therefore, healthcare systems commit significant effort to try and help these patients, unfortunately often with poor outcomes. The median survival of TP53mut MN is typically less than one year.
The scientific objective is to investigate a cellular process known as the spindle assembly checkpoint (SAC), which cancer cells use to survive when their
chromosomes
chromosomes:
The part of the cell that contains our DNA or genetic code.
are unstable. This is a hallmark feature of TP53mut MN. We believe that a SAC protein called KIF18A may be especially critical for the survival of TP53mut MN cells and may be a promising new drug target. This project will evaluate whether blocking KIF18A can kill TP53mut cells and make them more sensitive to an existing drug,
venetoclax
venetoclax:
Venetoclax is used to treat chronic lymphocytic leukemia or small lymphocytic leukemia in adults. Venetoclax is used alone or in combination with other cancer medicines to treat these conditions.
, which is effective in other MN but has shown limited effectiveness in TP53mut MN.
This work has the potential to significantly advance myelodysplastic syndrome care by uncovering a new weakness in one of its most aggressive blood cancers. In fact, a Pharmaceutical Company is conducting early-phase
clinical trials
clinical trials:
Clinical research is at the heart of all medical advances, identifying new ways to prevent, detect or treat disease. If you have a bone marrow failure disease, you may want to consider taking part in a clinical trial, also called a research study.
Understanding Clinical Trials
Clinical…
with their KIF18A inhibitor in advanced ovarian and breast cancers and have agreed to partner with the PI to evaluate this new drug in TP53mut MN. A necessary first step to this process before it can be used in humans for a new indication requires the experiments outlined in this proposal. The ultimate goal of this research is to produce a new, clinically relevant therapy that would benefit patients in the clinic.
In addition to the scientific and clinical goals, this award will provide Dr. Tessier with training in basic and translational cancer research. It will serve as a critical career step toward independence, preparing him to lead future clinical and laboratory studies aimed at improving treatment for patients with high-risk blood cancers.