Human epidermal growth factor receptor 2 (HER2) is overexpressed in over 20% breast cancers, and
to a lesser degree in gastric cancers, colorectal cancer, ovarian cancers and bladder cancers. In HER2+
tumors, HER2s are massively overexpressed and constitutively dimerized, leading to unrelenting
activation of down-stream proliferation and survival pathways and malignant phenotype. Because of the
high expression level of HER2, trastuzumab and pertuzumab, the two anti-HER2 monoclonal antibodies
are ineffective as monotherapy against these tumors. They need to be given in combinations with other
HER2-targeted therapy, chemotherapy or hormonal therapy. Here we will optimize and further improve
a novel HER2-mediated, peptide-based, and non-toxic transformable nano-agent that has been proven
to be highly efficacious as a monotherapy against HER2+ breast cancer xenograft models. This receptor-
mediated transformable nanotherapy is comprised of a peptide with unique domains that allow self-
assembly forming micelles under aqueous conditions and transformation into nanofibrils at the tumor site,
where HER2 is encountered. The resulting nanofibrillar network effectively suppresses HER2
dimerization, and downstream signaling leading to increased tumor cell death and complete remission of
the HER2+ tumors in xenograft models.
We recently reported the development of an ICG-derivatized nanoplatform that can deliver potent
immuno-stimulant imiquimod to the tumor sites in a 4T1 syngeneic breast cancer model, and we were
able to demonstrate that upon local light illumination (800nm) of the tumor, the photo-active micellar
nanoplatform was able to elicit a strong systemic anti-tumor immune response, particularly when given
in conjunction with anti-PD1 antibody. In addition to potent abscopal effects, this nano-photo-immuno-
therapeutic regimen was able to elicit strong immuno-memory against future tumor implants.
For this R01-IRCN proposal, we will apply some of the promising features of the two above mentioned
nanoplatforms, to generate a novel HER2-targeting transformable cancer targeting nanoplatform (TCTN)
that not only can directly suppress HER2 dimerization and signaling leading to tumor cell death, but can
also greatly augment systemic anti-tumor immune response. To achieve this, we will modularly
incorporate to the transformable nanoplatform HER2 binding ligands, T-cell and macrophage capturing
agents (e.g. LLP2A targets activated a4ß1 integrin of immune cells), galectin-1 inhibitor (e.g. LLS30) and
immunostimulant (e.g. resiquimod).
Aim 1. To design, synthesize, & characterize the novel transformable HER2-targeting TCTN
Aim 2. To use optical and MR imaging methods to determine the biodistribution of the TCTN constructs
in xenograft, PDX and syngeneic tumor models. To use the novel in-house developed EyePod intravital
imaging system to longitudinally evaluate, in real time, the intra-tumoral distribution and in situ
transformation of TCTN, cellular immune response, and tumor response of sub-retinal tumor implant.
Aim 3. To evaluate the therapeutic efficacy of TCTN in HER2+ PDX models of breast and gastric cancers.
Aim 4. To evaluate the immunotherapeutic efficacy of TCTN in an immunocompetent murine syngeneic
breast cancer model comprised of HuHER2-L2-Luc+ murine breast cancer cell lines implanted
orthotopically in MMTV.f.HuHER2 transgenic mice.