Interlaced Cytostatic Checkpoint Therapy
Interlaced Cytostatic Checkpoint Therapy is an innovation based upon Tau's innovative Cytostatic Checkpoint Therapy. Cytostatic Checkpoint Therapy (CCT) halts progression through the cell cycle by blocking calcium entry into cells at a critical “checkpoint”. The cell cycle has several checkpoints that act as sensors to determine whether the cell is prepared to progress to the next phase of the cycle. Growth factor activation of cells initiates a complex signaling process that culminates in passage of the initial checkpoint in the cell cycle—the G1/S checkpoint, also termed a restriction point. Although many cancer cells possess dysregulated checkpoint mechanisms, the entry of calcium from external media at the restriction point appears universally required and few, if any, cells appear to have developed a mechanism around it.
We have shown that the T-type calcium channel, CaV3, is the predominant entry mechanism through which extracellular calcium enters at the G1/S checkpoint. Virtually all growth factor receptors converge at this pathway and it is a “choke” point for proliferation. Importantly, the CaV3 channel is developmentally regulated being expressed ubiquitously in fetal tissues, but down regulated in most adult tissues except in pathological conditions. Thus pharmacological inhibitors of Cav3 slow tumor growth without significant effects on normal tissues.
A Maintenance Approach to Cancer
CCT is an innovative and unique chemotherapeutic approach. No other single approach exhibits such a broadly based blockade of growth factor activation resulting in cell cycle arrest at the G1/S checkpoint and inhibition of proliferation. As an independent modality, CCT markedly slows tumor growth thus reducing tumor burden. This cytostatic approach may provide a valuable adjunct to existing cytotoxic therapies of cancer by inhibiting residual tumor growth and tumor neovascularization. CCT could enable chronic treatment of cancer much as in diabetes, heart disease, and HIV infection. Like therapy for those diseases, CCT would not be a cure for cancer, but it would dramatically decrease the risk of dying from it.
An Acute Approach to Cancer
Making Chemotherapies Better - Interlaced Cytostatic Checkpoint Therapy -- Inhibition of calcium entry through Cav3 halts cell cycle progression just prior to the G1/S boundary, or checkpoint. This action results in an accumulation of cancer cells at this restriction point as individual, asynchronously dividing cells arrive at the checkpoint and are inhibited from entering S phase. We realized that many conventional cytotoxic chemotherapies exert their effect during S phase.
To solve the problem of making chemotherapies more targeted and more effective at killing the cancer cells, Tau created Interlaced Cytostatic Checkpoint Therapy. For example, temozolomide is an alkylating agent that methylates guanine residues in DNA. This makes the S phase abortive resulting in cell death. However, there are competing, endogenous repair pathways that restore DNA to its native state. We reasoned that increasing the fraction of cancer cells entering S phase would increase the fraction of cancer cells susceptible to the toxic effect of the various S phase cytotoxins, such as temozolomide. This is Interlaced Cytostatic Checkpoint Therapy. Administer an inhibitor of Cav3, such as mibefradil, for a brief time then withdraw it and immediately begin treatment with an S phase cytotoxin, such as temozolomide. In collaborative studies at Duke University Brain Tumor Center, we have found that interlaced miberadil/temozolomide treatment results in significantly enhanced tumor cell cytotoxicity and animal survival over temozolomide alone in animal models of GBM.