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Using HIF-1 Blockade to Improve Chemotherapy Efficacy in Human Breast Cancer
We recently demonstrated that radiation causes HIF-1 activation in tumors, inducing radioresistance through protection of tumor vasculature. Inhibiting this HIF-1 response caused near-complete destruction of tumor vessels and significantly improved radiosensitivity in several models. Because the radiation-induced HIF-1-stimulatory pathways we uncovered are also activated by many chemotherapeutic agents, this resistance mechanism may also be relevant for chemotherapy. We propose to study the role of HIF-1 in chemotherapy resistance by determining which agents activate HIF-1, whether response to these drugs is improved by HIF-1 blockade, and whether such a combination might improve treatment of breast cancer in a clinical trial.
We will treat breast cancer xenografts with the most commonly-used chemotherapeutics (4-OH-cyclophosphamide, doxorubicin, docetaxel, paclitaxel, or 5-FU), followed by real-time non-invasive analysis of fluorescent HIF-1 activity reporters. We will then combine these drugs with 2-methoxyestradiol (2ME2), a novel HIF-1 inhibitor, to test the theory that HIF-1 blockade will work best when combined with drugs causing the most HIF-1 activation. Both orthotopic tumors and syngeneic spontaneous metastases will be treated to gauge efficacy of these combinations in gross and systemic disease, respectively. In addition, a phase I clinical trial with biologic endpoints will be conducted to test the combination of HIF-1 inhibition and chemotherapy in human tumors. 15 patients with metastatic breast cancer will receive single agent weekly docetaxel, with HIF-1 inhibition added to the second docetaxel dose (day 8). Biopsies will be taken pre-treatment (day 0), after one week of docetaxel alone (day 8), and after one week of docetaxel plus 2ME2 (day 15). These sequential samples will be stained for HIF-1 and its downstream mediators (VEGF, GLUT-1, PAI-1) to analyze whether docetaxel activates this important pathway (increased signal at day 8 vs. day 0), and whether 2ME2 can abrogate this response (decreased signal at day 15 vs. day 8). We will also stain for markers of vascularity (CD31), proliferation (Ki-67), and apoptosis (TUNEL) in these samples to determine whether docetaxel plus 2ME2 (day 15) is significantly better than docetaxel alone (day 8) at deviating these biomarkers from baseline (day 0) in ways expected to associate with improved treatment outcome (i.e. lower vascularity, lower proliferation, higher apoptosis). These studies would strongly support a role for HIF-1 blockade in improving current breast cancer treatment.
The American Cancer Society estimates that over 40,000 women will die of breast cancer in 2005. The vast majority of these deaths will be attributable to metastatic disease which fails to respond to chemotherapeutic drugs. Exploring new ways to enhance breast cancer responsiveness to chemotherapy, then, has vast potential to impact mortality from this disease. We recently found that as breast tumors in mice are exposed to therapy, an important protein known as “HIF-1” is activated. Activation of HIF-1 leads tumors to resist damage caused by their treatment, limiting the overall efficacy of the therapy. We discovered that inhibiting the activation of HIF-1 in a treated tumor suppresses this resistance mechanism, leading to a significant improvement in treatment response. Tumors which were minimally responsive to single agent treatment had sustained growth suppression when combined with HIF-1 blockade.
Though these early studies were quite promising, they were performed using radiation, not chemotherapy, as the treatment modality. As mentioned above, chemotherapy is the treatment for breast cancer whose optimization offers the most potential to reduce mortality. Therefore, we would like to extend our studies to investigate whether HIF-1 blockade might enhance chemotherapy as it does radiotherapy. It is expected that this will be the case. Because of similarities in the effects on tumor biology caused by both treatment modalities, many chemotherapeutics should activate HIF-1 as does radiation. Moreover, the resistance mechanisms turned on by HIF-1 ought to attenuate damage caused by chemotherapy just as they do for radiation. Therefore, tumor sensitivity to chemotherapy might be augmented by concurrent HIF-1 blockade, improving our ability to treat breast cancer with chemotherapeutic drugs. We will use a combination of animal and human studies to investigate this hypothesis. These studies should allow us to determine which chemotherapy agents and HIF-1-inhibiting drugs work best together, readying this combination therapy for clinical application in the very near future.