NONMEM Users Network Archive

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[NMusers] Webinar: Attack of the Clones: Understanding the kinetics of resistance to cancer treatment

From: Rebecca Baillie <rbaillie_at_rosaandco.com>
Date: Fri, 13 Sep 2019 20:07:44 +0000

Attack of the Clones: Understanding the kinetics of resistance to cancer tr=
eatment
James Yates, MMath, PhD, Principal Scientist, AstraZeneca, Cambridge UK
Wednesday Sep 18, 2019, 12:00 to 1:00 pm EDT
Register for free at https://register.gotowebinar.com/register/409887749428=
3132684

Abstract:
Despite survival gains that have been made with targeted anti-cancer medici=
nes, patients ultimately relapse due to drug resistant disease. It is widel=
y understood that this is due to the presence of drug resistant cells prese=
nt in the tumour - a concept acknowledged since the 1970s. Acquired genetic=
 lability is required for cancer cells to express a phenotype that can esca=
pe both normal, homeostatically controlled, tissue turnover as well as evad=
e immune surveillance. Therefore, it is no surprise that some cancer cells =
will gain further advantage via drug resistance. The onset of this resistan=
ce will dictate the time to progression and ultimately death. It would ther=
efore be beneficial to anticipate the evolution of resistance in treated tu=
mours to inform the optimal treatment regimen, optimal sequence of treatmen=
ts, combination strategies and to prioritise mutations to target with new m=
edicines.
In this talk current knowledge of resistance kinetics in the clinic based u=
pon observations and model-based analyses will be reviewed. The question of=
 whether drug resistance is innate or acquired on treatment will be discuss=
ed as well as evidence for both processes. Using models of resistance kinet=
ics, the relationship between resistant disease, PFS and OS can be demonstr=
ated. These models can also be used to understand the optimal regimen to co=
ntrol resistant disease. However, an ongoing challenge is how to interrogat=
e clinical data that represent the "patient journey" through multiple lines=
 of therapy. This is important so that the influence treatment history has =
on the duration of response to subsequent treatment options can be understo=
od.
Moving back to animal models of cancer, a review of modelling of xenografte=
d tumour experiments reveals that similar resistance kinetics are observed.=
 This suggests that modelling assumptions of the relative fitness of drug r=
esistant vs sensitive cells can be tested along with modelling the impact o=
f spatially constrained solid tumour growth. An example of using in vitro d=
ata for different NSCLC EGFR driven mutants to predict clonal selection in =
vivo will be used to demonstrate these concepts. Thus, these nonclinical in=
 vitro and in vivo systems, coupled with mathematical modelling, could prov=
e to be useful tools for investigating clonal evolution.



Received on Fri Sep 13 2019 - 16:07:44 EDT

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