A phase II multi-center trial evaluating dual targeting of the PI3K/AKT and NOS pathways for treating metaplastic breast cancer (MpBC)

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ABSTRACT Metaplastic breast cancer (MpBC) is a rare subset accounting for <1% of all breast cancers. However, MpBC is a significant health challenge as it exhibits the most dismal prognosis of all breast cancers, even worse than triple-negative breast cancer (TNBC), with a survival rate of 8 months or less in patients with metastatic disease. Due to a lack of druggable targets, the main therapeutic option for metastatic MpBC remains systemic chemotherapy, despite known resistance to most cytotoxic drugs. One common molecular alteration in MpBC is hyperactivation of the phosphoinositide 3-kinase and protein kinase B (PI3K/AKT) pathway. Additionally, we recently published that MpBC displays a gain-of-function oncogenic mutation in ribosomal protein L39 (RPL39), which is responsible for treatment resistance, stem cell self-renewal, and lung metastasis. The mechanistic function of RPL39 is mediated through inducible nitric oxide synthase (iNOS)-mediated nitric oxide production. In addition, we demonstrated in a completed clinical trial that inhibiting this nitric oxide synthase (NOS) pathway using pan-NOS inhibitor NG-methyl-L-arginine acetate (L-NMMA) may represent a highly effective therapeutic option for TNBC patients. Therefore, we hypothesize that a combinatorial targeted approach of inhibiting the two major oncogenic pathways implicated in MpBC, PI3K/AKT and NOS, would lead to significant tumor regression. To test this hypothesis, this U01 application brings together research teams from Houston Methodist Cancer Center (HMCC), The University of Texas MD Anderson Cancer Center, and the National Cancer Institute (NCI). Specific Aim 1 seeks to define whether dual inhibition of PI3K/AKT using alpelisib and NOS inhibition using L-NMMA combined with nab-paclitaxel will increase the objective response rate and survival in metastatic MpBC patients. In Specific Aim 2, using blood and core biopsy tissues collected in the trial, we will identify mechanisms of response to therapy to determine the efficacy of the targeted PI3K/AKT and NOS pathway inhibitory approach. Furthermore, the cell-cell interactions among tumor cells, myeloid cells, lymphoid cells, and stromal cells within the tumor microenvironment and their role in supporting cancer stem cell populations and drug-resistant cell development during treatment will be evaluated. The impact of distinct cellular localization patterns within the tumor ecosystem on the process of cancer stem cell maintenance and modulation, as well as the development of drug resistance, will be analyzed at the single-cell level using spatial transcriptomics, immunofluorescence, CyTOF imaging systems, and a multi-modal data analysis model. This study thus proposes a mechanistic investigation of a combinatorial targeted approach against the two key pathways in MpBC, develops unique crosstalk models, and identifies biomarkers of resistance and cell–cell interactions using specimens derived from MpBC patients.