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mTOR Pathway

The mTOR pathway plays a major role in multiple critical cellular processes. Aberrant mTOR pathway activation is associated with a broad range of diseases and frequently driven by alterations in mTOR or other mTOR pathway genes like TSC1 and TSC2.

mtor-graphic

mtor-graphic

Inactivating alterations in TSC1 and TSC2 drive mTOR pathway activation and tumor growth

  • TSC1 and TSC2 form a tumor suppressor complex that down regulates mTOR activity
  • TSC1 and TSC2 alterations occur across a broad range of cancers including bladder cancer, kidney cancer, breast cancer, melanoma, and liver cancer
  • No therapies are approved for TSC1 and TSC2 alterations but numerous case reports show durable responses to mTOR inhibition
  • Standard CLIA-certified NGS panels already capture TSC1 and TSC2 alterations

Proposed rationale for nab-sirolimus use in patients with tumor-agnostic TSC1 and TSC2 inactivating alterations

  • Exploratory analysis of data in our AMPECT trial suggest responses to nab-sirolimus may occur in patients with TSC1 or TSC2 alterations
  • Data was generated in non-PEComa patients with TSC1 or TSC2 alterations in the ongoing Expanded Access Program (ASCO 2021 Abstract #339405)
  • In preclinical animal models, nab technology demonstrates greater mTOR pathway inhibition compared to currently approved mTOR inhibitors

Aadi has initiated a registrational trial in Tumor-Agnostic TSC1 & TSC2 Alterations: Learn more


nab Technology Platform

Aadi Bioscience’s lead investigational drug candidate product nab-sirolimus leverages albumin-bound nanoparticle technology.

product

nab-Sirolimus is based on a technology similar to ABRAXANE® (nab-paclitaxel; Abraxis Bioscience acquired by Celgene Corp in 2010)

Albumin accumulates in tumor tissues, either due to the leaky capillary system and defective lymphatic drainage of tumors or through an active gp60/caveolae-mediated transport process across tumor blood vessel endothelium. Importantly, albumin is taken up by proliferating tumor cells via endocytosis and macropinocytosis, then catabolized by lysosomal degradation to support de novo protein synthesis, energy, and tumor growth. The accumulation of albumin in solid tumors provides potential rationale for albumin-based drug delivery systems to preferentially target tumors.

Preclinical Differentiation vs. Existing mTOR Inhibitors

In preclinical animal models, the nab technology investigational drug candidate nab-sirolimus has demonstrated advantages over existing mTOR inhibitors including:

Acculmation
Increased Target
Tumor Growth

To Learn More Please Visit our Publications Page.