Exploiting Cancer’s Vulnerabilities
We are developing a pipeline of clinical candidates and researching novel approaches that target cancer cells at key points of vulnerability.
Genomic instability is a principal feature that drives the disease process of almost all cancers. We believe that the adaptation of cancer cells to this instability may represent a vulnerability that can be exploited for the design of cancer-cell specific therapeutics. While healthy human cells die with more than 46 chromosomes, cancer cells can survive with more than 100. In fact, more than 70% of cancer cells have an abnormal number of chromosomes – a state called aneuploidy – creating the opportunity for a pan-cancer strategy to selectively target diseased cells.
The targeting of proteins that function at the intersection of mitosis and DNA damage is a particularly attractive approach that has led to the discovery of two targets of interest:
- PLK4 (Polo-Like Kinase 4), an enzyme necessary for cancer cells to divide and multiply in the presence of increased chromosome count, is a key regulator of centriole duplication. PLK4 is frequently overexpressed in cancer cells and is associated with adverse survival outcomes. Inhibition of PLK4 has been shown to exacerbate genomic instability in cancer cells, forcing cell death.
- TTK/Mps1 (Tyrosine Threonine Kinase) is a conserved dual-specificity protein kinase, an enzyme essential for the maintenance of genomic stability during cell division. It is a critical regulator of the spindle assembly checkpoint (SAC), and its over–expression correlates with high grade in tumors and poor patient outcome. Inhibition of TTK allows cancer cells to progress through mitosis in the presence of misaligned chromosomes, resulting in eventual cell death.
We have designed and have now advanced into clinical development two first-in-class small molecules, designated CFI-400945 and CFI-402257, that potently inhibit PLK4 and TTK/Mps1, respectively. These candidates have shown promise in multiple investigator-sponsored clinical trials to date across a spectrum of highly aggressive cancers.
Treadwell’s candidates target critical steps in the cell cycle, killing genomically unstable and aneuploid cancers increasing
Historically, cancer treatments have primarily focused on either killing or arresting the growth of tumor cells. The pioneering work of one of our founders, Dr. Tak Mak, led to the discovery of immune cell checkpoint proteins and one of the central mechanisms by which cancer cells evade the body’s natural immune defenses. These checkpoints, including PD-1, PD-L1, and CTLA4, are key players in controlling the immune response. While the targeting of these checkpoints therapeutically has emerged as a novel, promising, and commercially successful approach to fighting a broad range of cancers, the clinical efficacy of checkpoint inhibitors has been quite limited to date. The vast majority of patients treated with checkpoint inhibitors don’t respond to therapy, or relapse after initially responding.
The Cancer Cell Immunity Cycle
Discoveries in our laboratories have led us to pursue a strategy of activating the immune system against tumors distinct from the PD-1/PD-L1 blockade and focusing on a novel target:
- HPK1 (Hematopoietic Progenitor Kinase 1, aka MAP4K1) is a kinase enzyme and a critical regulator of immune cell activation, antigen presentation, and T cell responses to immunosuppressive factors. Inhibition of HPK1 has been shown to activate T cells, B cells, and dendritic cells.
CFI-402411 is a novel, orally bioavailable inhibitor of HPK1, discovered through an intensive medicinal chemistry effort and developed by TIO Discovery scientists. Preclinical studies have demonstrated the promise of CFI-402411 as a potential monotherapy in both solid and hematological cancers, and in combination with existing checkpoint inhibitors. . It is our hope that CFI-402411 will provide a novel immuno-oncology strategy strongly differentiated from current therapies.
While pursuing these early successes, our research continues to further identify previously unexplored targets of therapeutic intervention for the most aggressive of cancers.