What anti-cancer therapies are being developed by TGF-beta scientists in the face of cancer "rebels"?

This property of TGF-beta makes it one of the most popular areas of research for tumor immunotherapy, and researchers hope to find new breakthroughs in tumor immunotherapy in these TGF-betas, which play a "military" role in promoting tumor development.
TGF-beta "mutiny" pre-transformation growth factor beta (TGF-beta) signaling path is a large family of multi-functional cytokines with many members, mainly by regulating cell growth, proliferation, differentiation, migration and apoptosis processes, involving the normal growth and development of mediated tissues and organs, the body's immune response and other biological processes.
TGF-beta activation and signaling (Photo Source: Reference 1) When human cells become cancerous, TGF-beta is secreted by the substring cells in the tumor microenta and macrophages in the tumor-immersion area.
in the early stages of tumor development, TGF-beta plays the role of an anti-cancer "military division."
TGF-beta's tumor suppression is derived from its ability to induce multiple gene expressions that are involved in inhibiting cell proliferation, inducing apoptosis, activating autophagy, inhibiting growth factor signals through substrate fibroblasts, inhibiting inflammation, and inhibiting angiogenesy.
these effects maintain a dynamic balance within normal tissues and prevent the early stages of tumor formation.
For example, it inhibits tumor cell proliferation by inducing the expression of autophagy-related proteins (4EBP1) and cell cycle protein-dependent kinase (CDK) inhibitors;
, however, the pressure exerted by TGF-beta on cancer cells before the mutation forces tumor cells to avoid the inhibition of TGF-beta, such as mutations.
surprising, TGF-beta, like "wall grass," "mutants" as tumors develop, which in turn "advises" cancer cells to avoid attacks on the tumor's microentasm immune system.
TGF-beta study after "rebellion" showed that TGF-beta after "mutiny" promotes tumors in many aspects.
it is like a "military division" to prepare for the curtain, in the tumor micro-environment on the "battleground" to give orders for the growth and metastasis of cancer cells to create various favorable conditions.
, TGF-beta signals act on immune cells in tumor micro-environments (TME).
On the one hand, secreted TGF-beta inhibits cytotoxicity of effect T cells and natural killer cells (NK), which weakens the anti-tumor capacity of the inherent immune cells in TME; The delivery and activation of F-beta inhibits the function of CD8-plus T cells, while the activated TGF-beta induces the expression of FOXP3 to differentiate the initial CD4-plus T cells into regulatory T cells, thus forming positive feedback and promoting tumor escape immunology supervision.
The effect of TGF-beta on immune cells (Photo Source: Resources) Second, TGF-beta signals can induce endocal-interstational transformation (EMT) by inducing the expression of transcription factors such as HMGA2, Snail1/2, and thus escape apoptosis.
EMT is an important pathological feature of tumor invasion and migration, and also a prerequisite for the spread of cancer cells.
, growth factors such as EGF and PDGF, which exist in micro-environments, also act together with TGF-beta to induce EMT.
addition, the increase in TGF-beta expression also promotes the secretion of factors such as VEGF-A and stimulates the production of new blood vessels, thus contributing to the growth and metastasis of cancer cells.
recent studies have also shown that TGF-beta signaling pathrases are also associated with drug resistance in tumor cells.
, for example, it can help tumor cells avoid the lethal effects of some chemotherapy drugs, and it can also enhance the resistance of tumor cells by increasing the expression of the protein kinase C alpha (PKC alpha).
thieves first king - based on TGF-beta anti-cancer thinking so-called thieves first king.
victory in this battle between humans and cancer, one treatment strategy is to target these TGF-betas, which play a "military" role in promoting tumor development.
Because TGF-beta involves many aspects of tumor development process, inhibiting TGF-beta signaling provides a number of research targets for anti-tumor therapy, which has also become a hot research and development field for new anti-cancer therapies.
As recently as August, BMS announced that it would acquire Forbius for the latter's TGF-beta research and development program, while Pioneer Pharmaceuticals announced that it would acquire an interest in PD-L1/TGF-beta dual-target antibodies in Greater China, a controlling subsidiary of Zeelyn Pharmaceuticals, for nearly $23 million.
comes after MSD announced plans to acquire Tilos Therapeutics, which regulates TGF beta.
TGF-beta-targeted drugs under development, TGF-beta mono-targeted drugs are a large category.
such as Novartis's recently approved clinical NIS793 in China, and Lilly and Company's galunisertib, are now in the mid-to-late stages of clinical life.
in China, there are also GFH018 tablets of Jinfang Pharmaceuticals and YL-13027 of Li Pharmaceuticals, which are currently undergoing Phase 1 clinical trials.
addition to monoantigenic drugs, dual-specific antibodies are also a popular research and development direction, with PD-L1/TGF-beta-dual anti-drugs as the majority.
PD-L1 is a programmed cell death complex, and PD-1/PD-L1 signaling pathps play an important role in the escape of tumor immunity.
PD-L1/TGF-beta-dual resistance can restore and enhance the body's anti-cancer response by simultaneously blocking the two immunosuppressive signaling path paths, PD-L1 and TGF-beta.
of these products, the german Merck KGaA's M7824 (bintrafusp alfa) is currently progressing rapidly and is undergoing Phase 3 clinical trials for advanced non-small cell lung cancer (NSCLC).
, the product has been approved for a number of clinical trials, for adaptive diseases such as NSCLC, bile tube cancer and cervical cancer.
addition, Hengrui Pharmaceutical's SHR-1701 injection, Pumis Bio's PM8001, pioneering pharmaceutical industry recently introduced GS19, etc. are PD-L1/TGF-beta dual specific antibodies.
addition, there are companies that develop cell therapy products for TGF-beta.
such as the CAR-T-19-DNR injection of Yongtai biology, its functional component is genetically modified expression of anti-CD19 chimed antigen receptor and explicit negative mutation TGF-beta II receptor T cells.
synchronous transcription translation of DNRII subjects expressed on the surface of CAR-T-19-DNR cells has the potential to inhibit the immunosuppressive effects caused by TGF-beta in tumor micro-environments and to prevent the weakening and depletion of the immune killing capacity of CAR-T-19-DNR cells.
thinking behind the development of TGF-beta inhibitors is noteworthy that previous studies have shown that TGF-beta monotherapy has a low response rate, which may be related to the fact that it is not a tumor driver.
, combination therapy has become one of the main development directions in this field, including in combination with immunosuppressants (e.g. PD-1/L1 antibodies), cytotoxic drugs, radiotherapy, cancer vaccines, etc.
, such as Lilly, is working on a combination of galunisertib and anti-PD-L1 antibody levels of durvalumab to treat patients with metastatic pancreatic cancer.
from the available clinical data, PD-L1 antibody and TGF-beta antibody combined anti-tumor effect is more obvious than single drug treatment.
, however, there are still many problems waiting to be solved in the development of new drugs in this area.
due to the diversity of TGF-beta signals, co-medication may be effective only if TGF-beta is promoting tumor signals.
the efficacy of anti-TGF-beta drugs needs to be carefully analyzed when TGF-beta plays a tumor suppressant role, or when the subject of TGF-beta mutates.
addition, co-medication may cause a strong immune response in patients, patient tolerance, and the deepening of side effects is also a question worth thinking about.
understanding the communication and interaction between various components and TGF-beta signals in tumor patients is the key to improve clinical efficacy in the future.
resources: s1. Rik Derrynck et al. TGF betabiology in cancer progression and immunotherapy. Nature Reviews Clinical Oncology (2020). [2] Constance J. Martin et al. Selective resedion of TGF beta 1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Science Translational Medicine (2020). Zhang Wei, Huang Tao, Mi Lizhi. TGF beta signals that depend on the micro-environment. China Journal of Biochemistry and Molecular Biology (2019). He Qingying, Zhang Xueyan. Advances in the study of the correlation between TGF-beta signaling pathrases and tumor resistance. Li Na, Rong Rong, Luo Yunping, etc. Treatment Strategies for Targeting Tumors and Tumor Micro-Environments . . . Basic Science in China, 2017 (3).