Targeted therapies for human cancers with copy number variations
P53 is inactivated in a majority of human tumors. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment due to the complexity of p53 signaling. Therefore, identification of vulnerabilities conferred by p53 deletion or mutation is a major challenge to target p53 aberrancy in human cancer. The Lu Lab’s recent work revealed that frequent hemizygous deletion of the p53 gene often encompasses a neighboring essential gene, POLR2A, rendering cancer cells vulnerable to further suppression of POLR2A. POLR2A encodes the catalytic subunit of RNA polymerase II complex, which can be specifically inhibited by α-Amanitin. α-Amanitin-based antibody drug conjugates (ADCs) are highly effective therapeutic agents with significantly reduced toxicity. Low doses of α-Amanitin-based ADCs lead to complete tumor regression in preclinical cancer models. In collaboration with physician and industrial scientists, the laboratory is now developing α-Amanitin-based drugs that specifically target human cancers with hemizygous loss of p53/POLR2A. This work was published in Nature, 2015 and was profiled by Nature Reviews Cancer, Nature Reviews Clinical Oncology, and Cancer Discovery.
In addition, the Lu Lab also identified USP13 (ubiquitin peptidase 13) as a potential target gene in human ovarian cancer. USP13 specifically deubiquitinates and thus upregulates ATP citrate lyase and oxoglutarate dehydrogenase, two key enzymes that determine mitochondrial respiration, glutaminolysis and fatty acid synthesis. The USP13 gene is co-amplified with PIK3CA in 29.3% of high-grade serous ovarian cancers and its overexpression is significantly associated with poor clinical outcome. Inhibiting USP13 remarkably suppresses ovarian tumor progression and sensitizes tumor cells to the treatment of PI3K/AKT inhibitor (Nature Communications, 2016).
Developed novel nanodrugs for cancer therapy
To eliminate the cancer stem cell (CSC) for cancer treatment, the laboratory has collaborated with biomedical engineering scientists to develop nanoscale biomaterials to safely and effectively deliver one or more small macromolecules including hydrophilic/hydrophobic anticancer drugs, proteins/peptides and siRNAs/miRNAs. For example, the Lu Lab has synthesized dual (temperature and pH) responsive polymeric nanoparticles to co-encapsulate both hydrophilic and hydrophilic drugs for targeting tumors and the drug resistance mechanisms of cancer (ACS Nano 2010 & 2015).
The laboratory has been working on combined cancer treatment of chemo, photodynamic and photothermal therapies. In the process, the laboratory has developed a biomimetic hybrid nanoplatform with a eukaryotic cell-like configuration (Nature Communications, 2015). Another example is the NIR-laser activatable “nanobomb” that was developed to encapsulate small RNAs with high efficiency (~85%) for cytosolic delivery (Advanced Materials, 2015).
NIH R01CA203737: Targeting human cancers with hemizygous deletion of TP53
NIH R01CA206366: Nanotechnology enabled targeting of p53 deficiency in human cancer
NIH R21CA213535: Engineering antibody drug conjugates to target p53-defective triple negative breast cancer
NIH R21CA185742: Ubiquitin specific peptidases as redox sensor in oncogene-induced p53 signaling
IU School of Medicine Strategic Research Initiative fund
Vera Bradley Foundation fund