Non-clinical Research

Ribosomal Biogenesis (RiBi) Inhibition and Immunogenic Cell Death (ICD)

Ribosomes, manufactured in the nucleolus through a process called ribosomal biogenesis (RiBi), are key to the synthesis of proteins necessary for cellular growth and division. Cancer cells require higher levels of ribosomal activity to survive and promote malignancy. Almost all cancer types display large and/or increased number of nucleoli, promoting greater cancer cell sensitivity to RiBi inhibition. Therefore, in contrast to healthy cells, cancer cells are much more vulnerable to the inhibition of RiBi.

Inhibition of RiBi in the nucleolus with PT-112 leads to organelle stresses (ER and mitochondria) that release specific Damage Associated Molecular Patterns (DAMPs). DAMPs are the hallmark of ICD, a unique form of cancer cell death that leads to activation of the immune response. By contrast, apoptosis is generally tolerogenic and does not lead to an immune response. DAMPs bind to specific Pattern Recognition Receptors (PRRs) on dendritic cells, leading to the presentation of tumor specific antigens and activation of effector T-cells. In addition to the adaptive immune response, PT-112 also activates the innate immune response via engagement of NK cells. This cascade of immune activation results in a robust and potentially durable immune response.

Inducing ICD in Mouse Models

PT-112’s induction of immunogenic cell death (ICD), is a rare mode of cancer cell death and an important component of an anti-cancer adaptive immune response. PT-112 has been shown to trigger the release of the hallmark DAMPs (HMGB1, calreticulin, ATP) from murine cancer cells. Further, a vaccine derived from murine cancer cells exposed to PT-112 in vitro protected 100% (n=10) immunocompetent mice against rechallenge with live cancer cells. As such, PT-112 is a small molecule anti-cancer agent that possesses immunotherapeutic properties (see OncoImmunology 2020).

Synergy with Immune Checkpoint Inhibitors

PT-112 offers promising combinatorial options with immune checkpoint inhibitors. Evidence to date in immune-competent mouse models demonstrates synergy with PD1, PDL1, and CTLA4 murine antibodies (see OncoImmunology 2020).

Biodistribution/Osteotropism

As a systemic therapy, PT-112 reaches relevant concentrations in tissues, such as liver and lung, and highest concentrations in mineralized bone.

Osteotropism has been demonstrated by sophisticated imaging studies shown below.