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Therapy evasion – and subsequent disease progression – is a major challenge in current oncology. An important role in this context seems to be played by various forms of cancer cell dormancy. For example, therapy-induced dormancy, over short timescales, can create serious obstacles to aggressive treatment approaches such as chemotherapy, and long-term dormancy may lead to relapses and metastases even many years after an initially successful treatment. The underlying dormancy-related mechanisms are complex and highly diverse, so that the analysis even of basic patterns of the population-level consequences of dormancy requires abstraction and idealization, as well as the identification of the relevant specific scenarios.
In this paper, we focus on a situation in which individual cancer cells may switch into and out of a dormant state both spontaneously as well as in response to treatment, and over relatively short time-spans. We introduce a mathematical ‘toy model’, based on stochastic agent-based interactions, for the dynamics of cancer cell populations involving individual short-term dormancy, and allow for a range of (multi-drug) therapy protocols. Our analysis shows that in our idealized model, even a small initial population of dormant cells can lead to therapy failure under classical (and in the absence of dormancy successful) single-drug treatments. We further investigate the effectiveness of several multidrug regimes (manipulating dormant cancer cells in specific ways) and provide some basic rules for the design of (multi-)drug treatment protocols depending on the types and parameters of dormancy mechanisms present in the population.
Between his arrival in Frankfurt in 1922 and and his proof of his famous finiteness theorem for integral points in 1929, Siegel had no publications. He did, however, write a letter to Mordell in 1926 in which he explained a proof of the finiteness of integral points on hyperelliptic curves. Recognizing the importance of this argument (and Siegel's views on publication), Mordell sent the relevant extract to be published under the pseudonym "X".
The purpose of this note is to explain how to optimize Siegel's 1926 technique to obtain the following bound. Let K be a number field, S a finite set of places of K, and f∈oK,S[t] monic of degree d≥5 with discriminant Δf∈o×K,S. Then: #|{(x,y):x,y∈oK,S,y2=f(x)}|≤2rankJac(Cf)(K)⋅O(1)d3⋅([K:Q]+#|S|).
This improves bounds of Evertse-Silverman and Bombieri-Gubler from 1986 and 2006, respectively.
The main point underlying our improvement is that, informally speaking, we insist on "executing the descents in the presence of only one root (and not three) until the last possible moment".