Tumor HypoxiaTreating Disease Through Tumor Selective Therapies
Tumor hypoxia, or low oxygen concentration, is a result of disordered vasculature found in all solid tumors. Whereas normal healthy tissues are typically well-oxygenated by virtue of having highly regular and structured arrays of blood vessels, the vasculature supporting cancerous tissues is highly disordered and irregular. Common abnormalities in tumor vasculature include a large variation in the distance between the blood vessels that carry oxygen and other vital nutrients as well as “dead-ends” and temporary occlusions. Furthermore, in tumors, the growth of malignant cells is unregulated resulting in these tissues literally outgrowing their blood supply, leading to severe deficiencies in the perfusion of oxygen and nutrients.
Together, abnormalities in tumor vasculature and the unregulated growth of cancer cells lead to distinctive hypoxic microenvironments not found in normal tissues. Many traditional anti-cancer agents are not able to penetrate into these hypoxic zones. Furthermore, cells that reside within regions of tumor hypoxia are relatively quiescent in contrast to highly proliferative cells that are the hallmark of cancer. As many traditional cancer therapies work by blocking cell division, they are not effective in killing the non-dividing, quiescent cells within hypoxic zones. It has also been demonstrated that cells subjected to prolonged hypoxia accumulate the changes in their growth properties and genetic mutations that can lead to drug resistance, enhanced metastatic potential, and, ultimately, treatment failure.
Given its central role in tumor progression, metastasis, resistance, and ultimately treatment failure, hypoxia is emerging as a significant, high-priority target for cancer therapy.
Most Advanced Therapeutic Candidate in Active Clinical Development from a New Class of Tumor Hypoxia-targeted Drugs
The introduction of therapies that selectively target tumor hypoxia offers the potential to selectively target tumors and expand the therapeutic options available for cancer patients across the majority of tumor types. To Threshold’s knowledge, TH-302 is the most clinically advanced hypoxia-targeted drug in active development for the treatment of cancer. Discovered by Threshold scientists, TH-302 is designed as a prodrug that is selectively activated under the extreme hypoxic conditions commonly found in tumors, but not typically in healthy tissues. Within regions of tumor hypoxia, TH-302 is converted to its active form, bromo isophosphoramide mustard (Br-IPM). Variants of IPM are clinically validated potent DNA alkylating agents, which kill tumor cells by causing DNA to crosslink thereby rendering cells unable to replicate their DNA and divide. Once activated in hypoxic tissues, Br-IPM can also diffuse into surrounding oxygenated regions of the tumor and kill cells there via a “bystander effect”.
Preclinical and clinical data suggest that TH-302 has significant anti-tumor activity both alone as well as in combination with other cancer therapies that target the rapidly proliferating cells found in normally oxygenated regions of solid tumors. Because of its preferential activation in the hypoxic regions of solid tumors, we believe that TH-302 will be less likely to produce the systemic toxicity caused by untargeted cytotoxic chemotherapies. Preclinical studies have also shown enhanced antitumor activity of TH-302 when combined with antiangiogenic agents. The underlying biological rationale for this enhanced activity is based, in part, on evidence that antiangiogenic agents increase levels of tumor hypoxia. Other research suggests that the bone marrow of patients with leukemia as well as multiple myeloma is also highly hypoxic and supports the potential therapeutic utility of TH-302 in treating these blood cancers.
To date, TH-302 has been investigated both as a monotherapy and in combination with chemotherapy treatments and other targeted cancer drugs in more than 700 patients with a broad spectrum of solid tumor types and blood cancers. Currently, the most advanced clinical study of TH-302 is a pivotal Phase 3 trial evaluating TH-302 in combination with doxorubicin in patients with soft tissue sarcoma. A second ongoing Phase 3 study is designed to evaluate TH-302 in combination with gemcitabine in patients with advanced pancreatic cancer. In addition, several early-stage clinical trials are evaluating the safety and efficacy of TH-302 in a variety of solid and hematologic tumors either as monotherapy or in combination with other anti-cancer agents. Read more about clinical studies of TH-302.
In February 2012, Merck KGaA signed a global agreement to co-develop and commercialize TH-302 with Threshold. Under the terms of the agreement, Merck KGaA received co-development rights, exclusive global commercialization rights with Threshold retaining an option to co-commercialize the therapeutic in the United States.
Investigational Hypoxia PET Imaging Agent
[18F]HX4 [flortanidazole (18F)] is an investigational radiolabeled hypoxia Positron Emission Tomography (PET) tracer developed by Siemens Healthcare Molecular Imaging to potentially identify and quantify the degree of hypoxia in tumors in vivo. PET is a nuclear medical imaging technique that non-invasively produces a three-dimensional image of functional processes in the entire body. PET is routinely used to inform physicians on diagnosis and treatment of cancer and is used in cancer treatment centers globally. [18F]HX4 has a 2-nitroimidazole “trigger” that is designed to be activated under the extreme hypoxic conditions generally found in tumors but not typically in normal healthy tissue. Clinical data has demonstrated the potential of [18F]HX4 to quantify the degree of hypoxia within different tumors.
In March 2013, Threshold announced the acquisition of [18F]HX4 from Siemens Healthcare. Threshold initially intends to develop [18F]HX4 to determine a patient’s tumor hypoxia profile, which may identify patients who will best respond to Threshold’s hypoxia-targeted therapeutics.