Improving CDK4/6 inhibition therapy for patients with liposarcoma by understanding resistance

PROJECT SUMMARY/ABSTRACT CDK4/6 inhibitors (CDK4/6i) have shown promise for the treatment of dedifferentiated liposarcoma (DDLS). Palbociclib received Breakthrough Therapy Status from the FDA in 2013, and because of our work was included in the NCCN guidelines for treatment of liposarcoma in 2017. We have defined the cellular and biochemical effects of these drugs in this disease and shown that cellular senescence underlies their clinical activity. Innate early resistance is associated with a failure of the drug to induce senescence, with cells remaining in a reversible quiescent state after treatment. However, adaptive resistance, which occurs after a patient responds to treatment even if there were senescent cells detected in an earlier biopsy is common. Overall, our work has provided new insights into how to enhance the efficacy of CDK4/6i through novel combinations. In this application, we will further investigate combination therapy to overcome resistance in DDLS, while performing in-depth landscape analyses into the biology of geroconversion, the process of arrested cells transitioning from a reversible quiescent state into an irreversible senescent state which enacts an inflammatory-provoking senescence associated secretory phenotype [SASP], and how it may contribute to adaptive resistance. Specifically, in Aim 1, we will conduct a phase Ib/II clinical trial rich in correlative science to evaluate the efficacy of palbociclib in combination with MEK inhibitor mirdametinib in patients with progressive DDLS. This trial builds upon previous insights obtained from cell lines and patient-derived xenograft (PDX) data that suggest suppressing physiological HRAS signaling can overcome innate resistance to CDK4/6i to induce geroconversion from a state of cell cycle arrest. The phase Ib portion will establish the safety, proper doses, and schedule of the drug combination, while the primary outcome of the phase II portion will be progression-free survival (PFS) rate at 18 weeks. Patients will undergo a pretreatment biopsy and an on-treatment biopsy at 1 month and, if still on treatment, at 6 months to help characterize the biochemical and cellular effects of treatment and senescence over time. In Aim 2, we will categorize the response of 20 genetically diverse DDLS PDX models to palbociclib alone and palbociclib plus mirdametinib to identify molecular signatures associated with the temporally acquired resistance to these therapies. We will perform a longitudinal landscape analysis of each tumor, evaluating the effects of the drugs on pools of cycling, quiescent and senescent cells, and their ability to induce the SASP program. We will identify models of adaptive resistance to both single-agent and combination therapy, interrogate these states both in bulk and at single-cell resolution to gain insight into inter- and intra-tumor heterogeneity, and elucidate how these drugs affect the evolution of cellular subpopulations (cycling, quiescent, senescent, and apoptotic cells). In sum, evolving the use of CDK4/6i via a rational scientific approach to combination therapies that is designed specifically to overcome innate resistance and prevent acquired resistance will benefit patients with unresectable DDLS and provide approaches that may be of value in other cancers as well.