Targeting of Doppel-axis to Control Lung Tumor Angiogenesis and Immunity

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Project summary Tumors, just like normal tissues, require blood vessels to receive nutrients and oxygen and to eliminate wastes and carbon dioxide. To ensure this blood supply, tumors create their own vascular beds from established blood vessels by a process called angiogenesis. This process plays a major role in tumor growth, survival, and invasiveness. Currently, various monoclonal antibodies (mAb) and small-molecular-weight drugs are used to restrain angiogenesis and starve tumors of nutrients. Bevacizumab and ramucirumab, for example, are two mAbs that inhibit angiogenesis-bevacizumab by binding with vascular endothelial growth factors (VEGF) and ramucirumab by blocking VEGF receptors (VEGFR). When used alone or in combination with chemotherapy, anti-angiogenic drugs slow down metastasis, stop disease deterioration, and extend the overall survival time of cancer patients. However, angiogenesis not only drives the growth of blood vessels in tumors, it also performs many important physiological functions in the body. The ‘good’ (physiological) angiogenesis regulates the thrombotic process, maintains vascular tone, and speeds up wound healing. Unfortunately, current anti-angiogenic drugs indiscriminately inhibit both good and ‘bad’ (tumor-directed) angiogenesis, thus resulting in blood-coagulation disorders, hypertension, hypothyroidism, proteinuria, and bowel perforation. In principle, it should be possible to reduce or eliminate many of the side effects of current anti-angiogenic drugs by blocking signaling molecules that are expressed only in tumor endothelial cells (TECs) but not in normal endothelial cells (NECs). Recently, we discovered that a prion-like protein called doppel is expressed only in TECs but not in NECs. In preliminary study, we showed that (i) doppel is expressed in both human and animal cancers; (ii) increased doppel expression in TECs (Dplhi-TECs) is associated with increased blood vessel density in tumors; (iii) doppel erasure from TECs and from mice (i.e., doppel knockout) reduces the number of vessels in tumors; (iv) anti-doppel mAb slows tumor growth in mice; and (v) doppel-knockout mice shows higher ratio of intratumoral CD8 versus regulatory T cells. Thus, we posit that Dplhi-TECs promote neoangiogenesis and create an immunosuppressive TME, and targeting of Dplhi-TECs using novel monoclonal antibodies increase the efficacy of chemo- and immune-therapies. We will test this assumption under three major sets of experiments: (i) elucidate the molecular mechanisms by which doppel activates neoangiogenesis and tumor progression in a spontaneous model of non-small cell lung carcinoma (NSCLC); (ii) assess the pharmacokinetics, pharmacodynamic and antitumor efficacy of anti-Doppel mAbs in KrasLSL-G12D;p53Frt/FRT mice in combination with chemotherapeutics; and (iii) assess how Dplhi-TECs control lung tumor immune microenvironment. This project has both basic and translational applicability, because we will understand the biology of Dplhi-TECs in tumor microenvironment as well use construct new mAbs to block this novel molecular target that has no known roles in physiological angiogenesis.