OncoMet™ Program

This program is based on a strategy of trying to exploit knowledge about how tumors adapt to problems for their survival imposed by their own growth. As solid tumors grow in bulk, often as a result of rapid, unrestrained cell division, they can outstrip their ability to be vascularized. This results in a microenvironment within the tumor in which oxygen and nutrients, especially glucose, become growth limiting because of reduced ATP production. This situation can occur for normal cells in transient stress situations, and programs for adaptation to such metabolic stress have evolved, e.g. via glucose sensor mechanisms which result in the induction of genes which increase glucose uptake and energy production by anaerobic glycolysis. Tumor cells however use these mechanisms on a chronic basis. This uncouples glycolysis from mitochondrial oxidative metabolism and from the other important role that mitochondria play in normal cells – induction of apoptosis for regulated cellular turnover. In addition, many malignant tumors have undergone mitochondrial DNA mutations which further contribute to aberrant mitochondrial function. Thus, the ability to target mitochondria in tumor cells could provide an avenue for pharmacologic intervention in cancer.

Another normal mechanism for adaptation to metabolic stress and in particular glucose starvation has evolved to deal with maintaining the critical role of a second important cellular organelle – the endoplasmic reticulum (ER), where membrane and secretory proteins are synthesized and transported in an ATP dependent process. Reductions in ATP levels secondary to hypoxia and lowered glucose result in an accumulation of misfolded proteins in the ER, and a failure to provide proteins essential for cell survival. In extreme conditions, apoptotic cell death is triggered. The adaptation to ER stress involves the induction of a variety of genes which orchestrate the Unfolded Protein Response (UPR). The UPR has several component mechanisms; some of these reduce protein translation and the burden of unfolded proteins, some directly inhibit apoptosis, so that the cells can survive, while other mechanisms promote metabolic adaptations. A critical component of the UPR is the induction of the glucose – regulated protein GRP78. This is an ER located calcium binding chaperone protein. In nonstressed cells, GRP78 binds to ER transmembrane sensor proteins PERK, IREI and ATF6, and maintains them in an inactive form. When unfolded proteins dissociate GRP78 from them, these sensor proteins send signals to the nucleus to trigger the UPR. Normal cells in a homeostatic microenvironment express low levels of GRP78, but can transiently induce it in situations of metabolic stress. In tumor cells however, recent evidence suggests that GRP78 is strongly and chronically induced, resulting in tumor proliferation, survival, metastasis and resistance to a variety of therapies. Thus, it appears that chronic up-regulation of the UPR and in particular GRP78 may represent a major adaptation mechanism for tumors as they grow in bulk and develop a chronic microenvironment of metabolic stress.

In order to attack these tumor metabolic adaptation mechanisms therapeutically, we adopted a screening strategy of searching for compounds which selectively killed tumor cells under conditions of metabolic stress. Initially, we screened chemical libraries for compounds that could kill tumor cells in vitro selectively in the absence of glucose using tumor cell lines. We then selected promising compounds and used medicinal chemistry approaches to obtain candidate molecules with adequate potency, metabolic stability and other characteristics. We also confirmed the ability of these compounds to kill tumors in animal cancer models. At this point, we carried out a further selection process of characterizing the mechanism of action of compounds of interest. This “reverse engineering” approach has been successful in identifying a chemical series which acts both to inhibit tumor cell mitochondrial function and also to inhibit GRP78. This series has been designated our OncoMet™ series of anticancer agents and ITX 2155 has been entered into preclinical development with the goal of filing an IND in 2008.

FusoVir™ Program

FusoVir™ is a potent therapeutic cancer therapy using an engineered herpes simplex virus-2 (HSV-2) licensed from Baylor College of Medicine. The principal anti-tumor mechanisms used by the virus are two-fold: a direct cytopathic effect and systemic immune effect. The first is produced as the virus propagates and spreads from initially infected tumor cells to surrounding tumor cells, achieving a progressively larger volume of distribution and enhanced tumor cell killing.  Lysed tumor cells then elicit the host anti-tumor immune response, mobilizing the powerful host immune function to shrink and distroy distant, metastatic tumors.

FusoVir™ has powerful advantages over many conventional cancer therapies. These viruses selectively replicate in and kill tumor cells without harming normal cells, avoiding the common and often severe toxicity of radiation and chemotherapy that damages non-cancer cells and suppresses the host immune system. It can also de-bulk non-resectable tumors that surgery is not feasible. FusoVir™ also has many advantages over other virotherapies. Its fusogenicity enables infected cancer cells to fuse with neighboring non-infected cancer cells in a rapid fashion, thereby achieving much higher potency. More significantly, enhanced cell fusion and lysis in the tumor also promote efficient antigen presentation, which triggers a potent host immune response against the tumor, ultimately magnifying the efficacy of FusoVir™ compared to non-fusogenic HSVs.

Preclinical studies with FusoVir™ have shown strong efficacy in a number of cancer models, including human xenograft based on subcutaneous, orthotopic and metastatic tumors (breast cancer, ovarian cancer, pancreatic cancer and renal cancer). In addition, strong cellular immunity against both primary and metastatic tumors has been demonstrated in immuno-competent syngeneic mouse models. Extensive studies in mice have shown that FusoVir™ is safe for in vivo administration. Thus, the powerful combination of FusoVir™ ‘s direct oncolysis and fusogenic properties coupled with its ability to trigger an anti-tumor response has yielded promising preclinical results. This program is currently in preclinical toxicology evaluation, with an IND expected in 2008.