Lead Molecule DTX-5500
Chromosome 9p21.3 is the most common chromosome deletion in cancer. The biology of this deletion has major clinical implications for patients as a ubiquitous pan-cancer genomic correlate of both the “cold” tumor-immune phenotype and primary resistance to immune checkpoint therapy.
The tumor suppressor genes methylthioadenosine phosphorylase (MTAP) and CDKN2A are the only genes within a large and common deletion at 9p21.3 whose dual loss of function is significantly correlated to cancer immunosuppression, poor response to immune checkpoint therapy, and worse patient survival.
MTAP and CDKN2A are immediately adjacent on chromosome 9 and hence difficult to separate genetically because of frequent co-deletion. Their respective functional roles are complementary in promoting cancer with evasion of anti-tumor immunity and loss of cell cycle growth control.
Loss of Two Tumor Suppressor Genes at 9p21.3
MTAP is a tumor suppressor gene that is a housekeeping enzyme involved in methionine and purine salvage. This pathway can be thought of as more of a superhighway than a pathway, with millimolar flux of MTA. Despite high concentrations inside cells, very little MTA is normally found extracellularly, and in the circulation is at low nanomolar levels.
Deletion of the MTAP Enzyme Breaks a Major Metabolic Pathway
Based on a large body of published research together with mechanistic studies from our scientific founder Dr Everett Stone, we conclude that MTAP loss as the primary driver of this profound cancer immunosuppression and clinical consequences of 9p21.3 deletion.
When MTAP activity is lost the enzyme substrate methylthioadenosine (MTA), builds up inside cancer cells, but most freely escapes the cancer cell where it exerts an inhibitory effect on the immune system, effectively blocking antitumor immunity.
MTA Mediated Immunosuppression
The immunosuppressive properties of MTA were first described over 40 years ago and are mediated through both adenosine receptor signaling and inhibition of the methyltransferase enzyme PRMT5, with preferential inhibitory effects on CD8+ killer T cells and NK cells.
MTA is not known to play a regulatory role in normal physiology and may be unique as a pathological immunosuppressant in cancer distinct from the canonical immunoregulatory pathways frequently co-opted to evade immune surveillance and antitumor immunity.
At Delta TpX we are addressing the genetically driven immunosuppression resulting from MTAP gene loss of function. This represents the largest targeted therapy opportunity in oncology.
Frequency of MTAP Gene Deletion in Cancer
Reactivation of Antitumor Immunity by MTA Depletion in the Tumor Microenvironment
Our product candidate DTX-5500 requires a companion diagnostic to identify patients that may benefit from treatment. We anticipate that MTA depletion with DTX-5500 will reboot antitumor immunity.
The ubiquitous nature of the 9p21.3 deletion as a genetic correlate of immunosuppression and poor outcomes supports a tissue-agnostic development path using the MTAP CDx for patient identification.