Sub journal of Science: Antibody drug+mushroom toxin, combined treatment of triple negative breast cancer

• by EVOMT
• 2021-03-22

　　Breast cancer is the most common type of cancer among women. According to the World Cancer Research Foundation, more than 2 million cases of breast cancer were diagnosed worldwide last year. In addition to different histological characteristics, different types of breast cancer also have different biological characteristics: whether there are estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and other receptors. These characteristics affect cancer characterization and the treatment required.

　　Three negative breast cancer accounts for about 15% of all breast cancer cases, usually affecting women under 40 years old and with BRCA1 gene deficiency. This kind of breast cancer only expresses low levels or does not express ER, PR or HER2 receptors, which is highly invasive, with a high recurrence rate and a low survival rate. Currently, the treatment methods for triple negative breast cancer are limited, mainly including chemotherapy and PARP inhibitors.

　　In recent two years, the US FDA has successively approved tumor immunocheckpoint suppression therapy for locally advanced or metastaticfile triple negative breast cancer, such as PD-1 and PD-L1 antibodies. However, due to the immune escape mechanism of tumors and the complexity of tumor microenvironment, immune checkpoint inhibition therapy is often not effective. Current clinical data show that only 10-20% of triple negative breast cancer patients respond well to immunotherapy.

　　The existing therapeutic drugs for HER2, such as the antibody trastuzumab and the related antibody drug conjugate T-DM1, are only effective for breast cancer with high HER2 positive expression (immunohistochemical staining 3+), but not effective for breast cancer with low HER2 expression (immunohistochemical staining IHC 1+or 2+), mainly including most triple negative breast cancer. The research and development direction of triple negative breast cancer drugs mainly focuses on two aspects: first, finding new target proteins. The most important progress is the clinical application of TROP-2 antibody. Compared with other breast cancer subtypes including HER2 positive, the expression of TROP-2 is much higher in hormone receptor positive/HER2 negative (HR+/HER2 -) and triple negative breast cancer. Overexpression of TROP-2 is also common in non small cell lung cancer (NSCLC).

　　The FDA accelerated the approval of Immunodiagnostics' sacituzumab govitecan (Trodelvy), which is the first antibody drug conjugate targeting the TROP-2 antigen. Trodervy is applicable to the treatment of recurrent or metastaticfile triple negative breast cancer that has spread to other parts of the body; The second is trastuzumab deruxtecan (Enhertu) from Daiichi Sankyo Company in Japan. They mainly increased the drug antibody ratio (DAR) in this antibody drug conjugate, thereby increasing the killing activity of the drug against tumor cells. This drug is mainly used for unresectable or metastaticfile HER2 positive breast cancer (having received two or more previous treatments based on anti HER2 regimen), and HER2 positive gastric cancer that has received treatment or metastasis. However, the treatment of all these drugs is not based on the precise treatment of triple negative breast cancer's own genes and genetic characteristics, and lacks the necessary biomarkers and predictability of therapeutic effects.

　　The team led by Xiongbin Lu from Indiana University School of Medicine and Simon Comprehensive Cancer Center published a research paper entitled "TP53 loss creations thermal vulnerability in colorectal cancer" on Nature in 2015. It was discovered for the first time that single copy deletion of one of the most important tumor suppressor genes in humans, TP53, is very common in various cancers, and the missing DNA fragments not only include TP53, but also other genes. They discovered one of the genes necessary for cell survival, POLR2A, which encodes the largest subunit of RNA polymerase responsible for messenger RNA synthesis and is also necessary for enzyme biochemical activity. The distance between TP53 and POLR2A on chromosome 17 is very close, so almost all cancer cells with a single copy deletion of TP53 carry a co deletion of the POLR2A gene, which makes the expression of POLR2A protein in cancer cells more than twice as low as in normal cells. Although the POLR2A of cancer cells is still sufficient to maintain their replication and survival, it is very sensitive to further POLR2A inhibition. This important discovery provides a new perspective for developing treatment options for TP53.

　　On February 10th, 2021, the team of Xiongbin Lu published a paper entitled "Targeted significance for HER2-low break cancer with 17p loss" in Science Translational Medicine. This study reported a new type of precision therapy drug for breast cancer with chromosome 17p deletion.

　　Based on the bioinformatics analysis of the breast cancer genome, this study found that most of the single copy TP53 deletion fragments actually contain the entire short arm (17p) of chromosome 17. 17p single copy deletion is very common in breast cancer, accounting for 51.6%, and 41.9% of triple negative breast cancer also has this deletion. In addition to the TP53 and POLR2A genes, the 17p fragment contains 908 genes (348 protein coding genes and other non coding RNA genes).

　　Recently, Scott Lowe and Yu Liu's research team revealed that 17p deletion in tumors is associated with tumor growth, metabolism, and metastasis. In this paper, Lu's research team has developed a new deconvolution computational biology tool, which can use the breast cancer gene expression database to analyze the invasion and activity of immune T cells in tumors. They found that 17p deletion is associated with low T cell infiltration and activity, as well as possible immune escape mechanisms, which explains why patients with this type of tumor have a shorter survival period.

　　Amanitin is a specific small molecule inhibitor of POLR2A, but due to its hepatotoxicity, it cannot be directly used as a clinical drug. Coupling Amanita alkaloid with specific tumor antibodies can significantly improve drug targeting and overcome its hepatotoxicity.

　　A novel antibody drug conjugate, T-Ama, utilizes the HER2 antibody trastuzumab to couple with Amanita. Although triple negative breast cancer is considered HER2 negative, it actually contains as many as 80% of tumors with low to moderate HER2 expression (IHC 1+or 2+). These triple negative breast cancer cells are not sensitive to the commonly used trastuzumab conjugated drug T-DM1, but the triple negative breast cancer cells with 17p deletion are very sensitive to the new drug T-Ama when HER2 is expressed at a low level, which is dozens or hundreds times higher than T-DM1yao.

　　In vivo drug experiments also confirmed that T-Ama has excellent anti-tumor activity against these triple negative breast cancer, and human cancer tissue transplantation tumor model showed that T-Ama can kill triple negative breast cancer with low level expression of HER2 of T-DM1 resistance. Another important point is that T-Ama kills tumor cells and induces immunogenic cell death. This allows T-Ama drugs to be used in combination with tumor immune checkpoint inhibitors, greatly enhancing the effectiveness of immunotherapy. The effect of T-Ama has been verified in the mouse model of triple negative breast cancer with complete immune system. Finally, the safety of T-Ama was demonstrated in mouse and crab eating monkey models.　　

   　　Since the treatment of triple negative breast cancer is limited, the research and development of T-Ama drugs is of great significance for clinical treatment. T-Ama drugs not only achieve precise treatment for tumors with low HER2 expression and 17p deletion, but also significantly improve the therapeutic efficacy of currently commonly used immune checkpoint inhibitors. It is also important to note that as a new type of drug, Amanita alkaloid toxin has a different mechanism of action from the previously commonly used microtubule inhibitors or DNA replication inhibitors in antibody conjugates. The activity of Amanita alkaloid toxin is independent of the replication and proliferation of cancer cells, and even tumor stem cells and drug-resistant tumor cells that are not actively replicating are sensitive to this toxin.

　　The US patent for this study has been approved, and the Xiongbin Lu team and their partner Heidelberg Pharmaceuticals of Germany are conducting conversion work and preclinical preparations to enable early clinical trials of T-Ama drugs.

　　Thesis link:

　　https://stm.sciencemag.org/content/13/580/eabc6894