Precision targeting of tumour-associated macrophages in triple negative breast cancer
Date
2023-05-08
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Abstract
Rinnavähk mõjutab maailmas ∼2.3 miljonit inimest, põhjustades igal aastal peaaegu 700 000 surmajuhtumit. Eestis diagnoositakse igal nädalal keskmiselt 16 uut rinnavähi juhtu ja 5 inimest kaotavad selle vähi tõttu oma elu. Rinnavähk on väga heterogeenne, mis tõttu jagatakse see ravi paremaks planeerimiseks erinevatesse alatüüpidesse. Kolmiknegatiivne rinnavähk (ingl. triple negative breast cancer, TNBC) on kõige agressiivsem alatüüp, mis moodustab kuni 20% kõigist juhtudest. Tavaliselt mõjutab see alla 50-aastaseid naisi, kes ei osale rutiinsel mammograafial; seetõttu on tihti kasvaja diagnoosimise hetkeks jõudnud areneda juba hilisesse staadiumisse. Kolmiknegatiivne tähendab, et see on negatiivne östrogeeni ja progesterooni retseptorite ning inimese epidermaalse kasvufaktori 2 suhtes. Seetõttu on sellel rinnavähi tüübil vähem ravivõimalusi, kui teiste alatüüpide puhul. Keemiaravi ravimid üksinda pole spetsiifilised, mis tähendab, et need mõjutavad vähiravi ajal kogu keha. TNBC muudab organismi enda immuunsüsteemist pärinevad makrofaagid kasvaja poolt spetsiaalseteks makrofaagideks, mida nimetatakse kasvajat toetavateks makrofaagideks, mis aitavad kasvajal kasvada, metastaaseeruda ja kõrvale põigata keha normaalse kaitseliini, T-lümfotsüütide, eest. Selles doktoritöös kõrvaldasime me kasvajat toetavad makrofaagid või muutsime need kasvajavastasteks makrofaagideks ja uurisime, mis mõju see avaldab kasvaja progresseerumisele ja positiivse immuunvastuse aktiveerumisele. Selleks kavandasime ja arendasime välja uued ühendid, mis suunavad ravimid täpselt kasvajat toetavatesse makrofaagidesse, kuna nende küljes on peptiid, mis on spetsiifiline ainult nendele makrofaagidele. Meie peptiidipõhistel ühenditel oli terapeutilise mõju, nad aktiveerisid immuunsüsteemi ning olid ohutumad ja tõhusamad kui tavaline keemiaravi. Tulevikus näeme, et meie välja töötatud peptiid-juhitavaid ühendeid saaks kasutada kombinatsioonis teiste ravimeetoditega selle kliiniliselt raske haiguse ravimiseks.
Breast cancer affects ∼2.3 million people world-wide, leading to almost 700 000 deaths each year. In Estonia, on average 16 people are getting a breast cancer diagnosis every week and 5 people die because of it. Breast cancers are very heterogenous and are divided into different subtypes. Triple negative breast cancer (TNBC) is the most aggressive subtype comprising up to 20% of all cases. It usually affects women under 50 years old who do not attend routine mammography; therefore, the tumour is often at a late stage at the time of diagnosis. Triple negative means that it is negative for oestrogen and progesterone receptors and to human epidermal growth factor 2. This results in fewer treatment options than with other breast cancer subtypes, leaving many patients without any good options. Moreover, chemotherapy drugs on their own are not specific, meaning they will affect whole body during cancer treatments. In TNBC, macrophages from the body’s own immune system are converted by tumour into special type of macrophages called pro-tumoural macrophages that help tumours to grow, metastasise and to escape the attack from body’s normal line of defence, T lymphocytes. Here, we eliminated those pro-tumoural macrophages or converted them into anti-tumoural macrophages and studied the effect on tumour progression and the activation of a positive immune response. For that we designed and developed new compounds to precisely guide drugs to pro-tumoural macrophages by coupling the drugs to a guiding peptide. Our peptide-guided therapies led to therapeutic effect, activation of the immune system and were safer and more effective than conventional chemotherapy. For the future we envisage the use of our peptide-guided compounds in combination with other treatments to treat this clinically difficult to manage disease.
Breast cancer affects ∼2.3 million people world-wide, leading to almost 700 000 deaths each year. In Estonia, on average 16 people are getting a breast cancer diagnosis every week and 5 people die because of it. Breast cancers are very heterogenous and are divided into different subtypes. Triple negative breast cancer (TNBC) is the most aggressive subtype comprising up to 20% of all cases. It usually affects women under 50 years old who do not attend routine mammography; therefore, the tumour is often at a late stage at the time of diagnosis. Triple negative means that it is negative for oestrogen and progesterone receptors and to human epidermal growth factor 2. This results in fewer treatment options than with other breast cancer subtypes, leaving many patients without any good options. Moreover, chemotherapy drugs on their own are not specific, meaning they will affect whole body during cancer treatments. In TNBC, macrophages from the body’s own immune system are converted by tumour into special type of macrophages called pro-tumoural macrophages that help tumours to grow, metastasise and to escape the attack from body’s normal line of defence, T lymphocytes. Here, we eliminated those pro-tumoural macrophages or converted them into anti-tumoural macrophages and studied the effect on tumour progression and the activation of a positive immune response. For that we designed and developed new compounds to precisely guide drugs to pro-tumoural macrophages by coupling the drugs to a guiding peptide. Our peptide-guided therapies led to therapeutic effect, activation of the immune system and were safer and more effective than conventional chemotherapy. For the future we envisage the use of our peptide-guided compounds in combination with other treatments to treat this clinically difficult to manage disease.
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Keywords
animal models, breast cancer, chemotherapy, macrophages, immunotherapy