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Prostate cancer from cold to hot: exploring chances to enhance immunity or cut off insensitivity

Immunotherapy has dramatically improved outcomes for some types of cancer. But prostate cancers are typically immune cold, which means these patients have benefited little from immunotherapies. Finding a way to rev up the immune response would create tremendous opportunity to improve patient outcomes. Researchers led by the University of Michigan Rogel Cancer Center started with a simple thread: an inhibitor that showed promise against metastatic castration-resistant prostate cancer cells. This is the most challenging type of prostate cancer that has become resistant to hormone-based therapy. From there, they continued to untangle the web to discover multiple levels of cellular processes that were preventing the immune system from mounting a response. Break past them with this inhibitor and suddenly what’s considered an immune cold tumor turns red hot. Researchers started by screening a library of 167 inhibitors against prostate cancer cells. They found one, ESK981, had the most impact. ESK981 is a class of drugs called multi-tyrosine kinase inhibitors, which are designed to hit multiple targets.

This means it functions like a combination therapy, able to block cancer on more than one front. It was originally developed to check blood vessel growth and has already been tested in phase 1 clinical trials, which found it to be safe and well-tolerated. In cell lines and mice with metastatic castration-resistant prostate cancer, researchers found ESK981 inhibited tumor growth. Delving into the drug’s mechanism, scientists discovered several cellular processes were occurring. First was the role of a type of cell death called autophagy. The authors surprisingly found that ESK981 was a potent inhibitor of autophagy in tumor cells. This caused the cancer cells to produce a protein called CXCL10, which led to recruitment of immune T cells to the tumor. But there was one more layer to go. Ultimately, they traced it back to PIKfyve, a type of protein called a lipid kinase that beloing to the family of PI-3K, a protein kinase involved in cellular signaling for proliferation and death suppression. The authors discovered that ESK981 directly targets PIKfyve, affecting these multiple processes involved in metabolism and cell death.

The researchers confirmed this by knocking down PIKfyve in cell lines and mice. They saw the same processes occur: tumors stopped growing, autophagy was controlled and more T cells were recruited to the tumor. When they added an immune checkpoint inhibitor to the PIKfyve knockdown, the impact was even greater, significantly reducing tumor size. Based on these findings, researchers have begun phase 2 clinical trials using ESK981 alone or in combination with the immunotherapy nivolumab for metastatic castration-resistant prostate cancer. Overcoming resistance to immunotherapy is an urgent need in prostate cancer. The researchers deem that PIKfyve is a promising target, especially combined with an immune checkpoint inhibitor. This combination has potential to extend the benefit of immunotherapy to patients whose tumors have previously not responded. But it is apparently not the only way that is being pursued for prostate cancer to be made visible or “hot” to the immune system.

Another research team from Sun Yat-sen University of China, Guangdong, is investigating from another side of the same principle: DNA repair systems associated with immunological visibility. In their retrospective study, the researchers analyzed the expression of the PD-L1 protein in 33 tumor biopsy samples from patients. In vitro prostatic K cell lines were also used for biological examinations and investigating cellular mechanisms. One of the main chemotherapy drugs for prostate cancer is docetaxel (DTX), a cell cytoskeleton disruptor. In response to its presence, cellular gene expression is altered. One of the genes that has been seen to be induced by docetaxel in prostate cancer is that of the PD-L1 protein. This effect is blocked by the inhibition of the ATM protein, suggesting that it plays a central role in the expression of the PD-L1 receptor induced by docetaxel. ATM is a protein kinase that is activated following exposure to ionizing radiation, but also to oxidative stress, while NEMO is a regulator of the nuclear factor NF-kB that cancer cells use to escape cell death.

The same, however, is employed by immune cells to control the antibody response and the synthesis of regulatory cytokines. The use of cell lines in vitro allowed the researchers to confirm that the ATM protein stabilizes a second protein called NEMO, which in turn stabilizes the nuclear factor NF-kB to make it express PD-L1. Using an experimental prostate K mouse model, the team further proved that a combination of ATM and NEMO inhibitors together with DTX increases the efficacy of chemotherapy, an effect that is comparable to antibody alone against PD-L1. Then, the researchers discovered a mechanism whereby it is the anticancer drug itself that triggers an immune evasion of the tumor. Fortunately, experimental inhibitors of both ATM and NEMO are available in the laboratory. Therefore this information will help clinical oncologists to review the current protocols of anticancer chemotherapy and immunotherapy, adapting them and increasing the chances of counteracting resistant forms of prostate cancer.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Qiao Y et al., Chinnaiyan AM. Nature Cancer 2021 Aug 2.

Wang Z et al. J Immunother Cancer 2021 Jul; 9(7):e001758.

Zhang Y et al. PNAS USA. 2021 Jun; 118(24):e2103240118. 

Runcie KD, Dallos MC. Curr Oncol Rep 2021 Jun 14; 23(8):88. 

Palmbos PL et al. Clin Cancer Res. 2021 Jun; 27(11):3017-27. 

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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