Reshaping the landscape of locoregional treatments for breast cancer liver metastases: A novel, intratumoral, p21-targeted percutaneous therapy increases survival in BALB/c mice inoculated with 4T1 triple negative breast cancer cells in the liver

Patients with disseminated metastatic disease from breast cancer are
likely to have liver involvement in >50% of cases at some point
during disease progression. These patients have a poor prognosis; and,
when treated with the standard of care systemic therapy they have a median
survival of <9-months. Increasing survival in breast cancer
patients will likely require the administration of better therapies that
are specifically targeted to treat distant metastases. One approach to
increasing treatment efficacy for breast cancer liver metastases is
through the application locoregional therapies. Locoregional therapies are
an appealing interventional approach for breast cancer patients with liver
metastases since these tumor lesions are accessible via minimally invasive
procedures that can be administered using either ultrasound or CT imaging.
Current locoregional therapies to treat breast cancer liver metastases are
non-specific and have not produced significant increases in survival. The
goal of this study was to design and test a targeted locoregional
therapeutic intervention for breast cancer liver metastases. The lead
candidate, a fixed-dose small-molecule drug called MBC-005, was tested in
vitro and then the efficacy was evaluated in a BALB/c mouse liver
metastases model. A novel formulation of N-allyl noroxymorphone
hydrochloride incorporated into an alginate-based gel overcomes many of
the limitations associated with the administration of small-molecule
drugs, which include solubility, off-target toxicity, and enzymatic
degradation. In vitro results demonstrated that MBC-005 mediated its
anti-tumorigenic effect through a p21-dependent mechanism via a novel
molecular pathway, in which N-allyl noroxymorphone component of MBC-005
stimulated the opioid growth factor receptor to increase p21 expression.
Intratumoral administration of MBC-005 increased survival 3.9-fold in mice
and significantly decreased tumor volume 4-fold. While many cytotoxic
therapies increase p21 expression as a response to DNA damage, MBC-005
increased p21 expression independent cytotoxic DNA damage. MBC-005 did not
induce off-target toxicity; and, as such, would be amenable to multiple
rounds of administration. Nevertheless, it is notable that the positive
effects of MBC-005 treatment on increasing survival and decreasing tumor
volume in mice was achieved using a single dose.