Evaluation of bone metastases heterogeneity in metastatic prostate cancer

Turk, Maruša (author), Jeraj, Robert (mentor)

The treatment response of metastatic castration-resistant prostate cancer (mCRPC) to systemic therapies is affected by the evolution of resistance. Diverse levels of therapy resistance lead to heterogeneity of the treatment response, with some metastatic lesions, or even parts of lesions, that respond and some that do not respond. Evaluating treatment response heterogeneity is an important element based on which treatment strategies could be optimized. This thesis aimed to investigate the evolution of resistance and treatment response heterogeneity in mCRPC patients during their treatment course. To examine this objective, we developed a simple top-down computational model built on molecular imaging data of mCRPC patients treated with first-line (mCRPC-1) or subsequent-line (mCRPC-2) therapy. Ordinary differential equations simulated the dynamics of individual lesions, their response and the formation of new lesions. The model included only key kinetic parameters describing lesion growth, intrinsic and acquired resistance, the incidence of new lesion development and treatment efficiency. By examining the evolution of resistance and treatment response heterogeneity, the proportions of lesions comprising entirely of drug-resistant cells and nonfavourable responding lesions were extracted. Regarding mCRPC-1 patients, the proportion of nonfavourable responding lesions was low (median=0.45) even after 30 months of therapy, while the proportion of lesions comprising entirely of drug-resistant cells was high (median=0.96) after 18 months of therapy. Most of the mCRPC-2 lesions had a high proportion of nonfavourable responding lesions (median=0.68) and a high proportion of lesions comprising entirely of drug-resistant cells (median=1) were predicted after 5 months of therapy. Together, the findings revealed that some lesions with favourable treatment responses comprised entirely drug-resistant cells. This work demonstrates that our computational model can identify therapy-resistant lesions before they show clinical evidence of progression. These lesions should receive additional or new therapy before they show progression. However, our results require further confirmation in independent clinical studies.

• Language: English
• Keywords: metastatic prostate cancer, computational modelling, tumour heterogeneity, interpatient treatment response heterogeneity, intrapatient treatment response heterogeneity, resistance
• Work type: Doctoral dissertation
• Typology: 2.08 - Doctoral Dissertation
• Organization: FMF - Faculty of Mathematics and Physics
• Year: 2022
• PID: 20.500.12556/RUL-142379
• COBISS.SI-ID: 126350339
• Publication date in RUL: 04.11.2022

Secondary language

• Language: Slovenian
• Title: Ovrednotenje heterogenosti kostnih metastaz pri bolnikih z rakom prostate

Abstract

Terapevtski odziv metastatskega, na kastracijo rezistentnega raka prostate (mKRRP) je odvisen od razvoja rezistence. Različne ravni rezistence na terapijo privedejo do heterogenosti v odzivu na zdravljenje – z nekaterimi metastatskimi lezijami ali samo deli lezij, ki se odzivajo, in nekaterimi, ki se ne. Preučevanje heterogenosti v odzivu na zdravljenje lahko pomembno vpliva na optimizacijo strategij zdravljenja. Splošni cilj doktorske dizertacije je bil preučiti razvoj rezistence in heterogenost odziva na zdravljenje pri bolnikih z mKRRP tekom zdravljenja. Za dosego omenjenega cilja smo razvili enostaven računalniški model od zgoraj navzdol, osnovan na molekularnih slikovnih podatkih bolnikov z mKRRP, zdravljenih z zdravilom prvega (mKRRP-1) in neprvega izbora (mKRRP-2). Z navadnimi diferencialnimi enačbami smo simulirali dinamiko posameznih lezij, njihov odziv in nastajanje novih lezij. Model vsebuje le ključne kinetične parametre, ki opisujejo rast lezij, intrinzično in pridobljeno rezistenco, pojavnost novi lezij in učinkovitost terapije. S preučevanjem evolucije rezistence in heterogenosti odziva na zdravljenje smo izluščili delež lezij, v katerih so prisotne le rezistentne celice, in delež na terapijo neugodno odzivajočih lezij. Pri bolnikih z mKKRP-1 je bil delež na terapijo neugodno odzivajočih lezij tudi po 30 mesecih zdravljenja nizek (mediana=0.45), medtem ko je bil delež lezij, v katerih so prisotne le rezistentne celice visok (mediana=0.96) že po 18 mesecih zdravljenja. Za večino bolnikov z mKRRP-2 je bil že po 5 mesecih zdravljenja napovedan visok delež tako na terapijo neugodno odzivajočih lezij (mediana=0.68) kot tudi lezij, v katerih so prisotne le rezistentne celice (mediana=1). Rezultati nakazujejo, da obstajajo lezije, ki se ugodno odzivajo na zdravljenje, a sestojijo le iz rezistentnih celic. Pokazali smo, da naš računalniški model lahko prepozna lezije, ki so rezistentne na terapijo, še preden le-te kažejo klinične znake napredovanja. Takšne lezije bi morale prejeti dodatno ali novo zdravilo, preden kažejo znake napredovanja. Naši rezultati potrebujejo nadaljnjo potrditev v neodvisnih kliničnih študijah.

• Keywords: metastatski rak prostate, računalniško modeliranje, heterogenost tumorja, heterogenost v odzivu na zdravljenje med pacienti, heterogenosti v odzivu na zdravljenje med lezijami, rezistenca