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.