In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics.DOI: http://dx.doi.org/10.7554/eLife.00747.001

The extent of heterogeneity of driver gene mutations present in naturally occurring metastases is largely unknown, i.e. treatment-naïve metastatic disease. To address this issue, 60× whole genome sequencing of 26 metastases from 4 patients was carried out. We found that the identical driver gene mutations were present in every metastatic lesion of each patient studied. Passenger gene mutations not known or predicted to have functional consequences accounted for all intratumoral heterogeneity. Even with respect to these passenger gene mutations, the genetic similarity among the founding cells of metastases was markedly higher than that expected for any two cells randomly taken from a normal tissue. The uniformity of driver gene mutations among metastases in the same patient has critical, encouraging implications for the success of future targeted therapies in advanced stage disease.

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Abstract.We present a general framework for applying machine-learning algorithms to the verification of Markov decision processes (MDPs). The primary goal of these techniques is to improve performance by avoiding an exhaustive exploration of the state space. Our framework focuses on probabilistic reachability, which is a core property for verification, and is illustrated through two distinct instantiations. The first assumes that full knowledge of the MDP is available, and performs a heuristic-driven partial exploration of the model, yielding precise lower and upper bounds on the required probability. The second tackles the case where we may only sample the MDP, and yields probabilistic guarantees, again in terms of both the lower and upper bounds, which provides efficient stopping criteria for the approximation. The latter is the first extension of statistical model-checking for unbounded properties in MDPs. In contrast with other related approaches, we do not restrict our attention to time-bounded (finite-horizon) or discounted properties, nor assume any particular properties of the MDP. We also show how our techniques extend to LTL objectives. We present experimental results showing the performance of our framework on several examples.

Quantitative generalizations of classical languages, which assign to each word a real number instead of a boolean value, have applications in modeling resource-constrained computation. We use weighted automata (finite automata with transition weights) to define several natural classes of quantitative languages over finite and infinite words; in particular, the real value of an infinite run is computed as the maximum, limsup, liminf, limit average, or discounted sum of the transition weights. We define the classical decision problems of automata theory (emptiness, universality, language inclusion, and language equivalence) in the quantitative setting and study their computational complexity. As the decidability of the language-inclusion problem remains open for some classes of weighted automata, we introduce a notion of quantitative simulation that is decidable and implies language inclusion. We also give a complete characterization of the expressive power of the various classes of weighted automata. In particular, we show that most classes of weighted automata cannot be determinized.

Most specification languages express only qualitative constraints. However, among two implementations that satisfy a given specification, one may be preferred to another. For example, if a specification asks that every request is followed by a response, one may prefer an implementation that generates responses quickly but does not generate unnecessary responses. We use quantitative properties to measure the "goodness" of an implementation. Using games with corresponding quantitative objectives, we can synthesize "optimal" implementations, which are preferred among the set of possible implementations that satisfy a given specification. In particular, we show how automata with lexicographic mean-payoff conditions can be used to express many interesting quantitative properties for reactive systems. In this framework, the synthesis of optimal implementations requires the solution of lexicographic mean-payoff games (for safety requirements), and the solution of games with both lexicographic mean-payoff and parity objectives (for liveness requirements). We present algorithms for solving both kinds of novel graph games.

Quantitative generalizations of classical languages, which assign to each word a real number instead of a boolean value, have applications in modeling resource-constrained computation. We use weighted automata (finite automata with transition weights) to define several natural classes of quantitative languages over finite and infinite words; in particular, the real value of an infinite run is computed as the maximum, limsup, liminf, limit average, or discounted sum of the transition weights. We define the classical decision problems of automata theory (emptiness, universality, language inclusion, and language equivalence) in the quantitative setting and study their computational complexity. As the decidability of the language-inclusion problem remains open for some classes of weighted automata, we introduce a notion of quantitative simulation that is decidable and implies language inclusion. We also give a complete characterization of the expressive power of the various classes of weighted automata. In particular, we show that most classes of weighted automata cannot be determinized.

In this paper, we consider termination of probabilistic programs with real-valued variables. The questions concerned are:1. qualitative ones that ask (i) whether the program terminates with probability 1 (almost-sure termination) and (ii) whether the expected termination time is finite (finite termination); 2. quantitative ones that ask (i) to approximate the expected termination time (expectation problem) and (ii) to compute a bound B such that the probability to terminate after B steps decreases exponentially (concentration problem).To solve these questions, we utilize the notion of ranking supermartingales which is a powerful approach for proving termination of probabilistic programs. In detail, we focus on algorithmic synthesis of linear ranking-supermartingales over affine probabilistic programs (APP's) with both angelic and demonic non-determinism. An important subclass of APP's is LRAPP which is defined as the class of all APP's over which a linear ranking-supermartingale exists.Our main contributions are as follows. Firstly, we show that the membership problem of LRAPP (i) can be decided in polynomial time for APP's with at most demonic non-determinism, and (ii) is NP-hard and in PSPACE for APP's with angelic non-determinism; *[Copyright notice will appear here once 'preprint' option is removed.] moreover, the NP-hardness result holds already for APP's without probability and demonic non-determinism. Secondly, we show that the concentration problem over LRAPP can be solved in the same complexity as for the membership problem of LRAPP. Finally, we show that the expectation problem over LRAPP can be solved in 2EXPTIME and is PSPACE-hard even for APP's without probability and non-determinism (i.e., deterministic programs). Our experimental results demonstrate the effectiveness of our approach to answer the qualitative and quantitative questions over APP's with at most demonic non-determinism.