Investigations into Therapeutic Dose-Response / Heterogeneity
Frustrating the goal of sustained therapeutic efficacy against cancer is the shifting nature of tumor response. These shifts are a natural consequence of tumor heterogeneity. Some of these shifts can be a direct result of treatment itself, occurring because as treatment progresses, tumor subpopulations are differentially affected, altering the overall character of the tumor that faces further increments of the same regimen. In the simplest case, an acute dose can preferentially spare more resistant tumor subpopulations, which will result in a tumor that is less responsive to the same dose when given soon thereafter. But this type of resistance is highly dynamical, suggesting that if a dose schedule is spread out into smaller, uniform, regularly-spaced doses, i.e., ‘metronomically’, a better overall outcome might be attained. Early experiments by Browder et al. in mice confirmed an improved outcome, showing that even a drug to which a tumor population had become resistant under acute delivery could regain efficacy when delivered metronomically. An argument presented then for the improved efficacy was a shift in the drug target from the tumor parenchyma to the tumor stroma, specifically the supporting neovasculature. Collaterally, the milder dose increments were observed to be less toxic to the host, opening the door for higher levels of agent to be delivered safely and for benefit to improve yet further. In this way, metronomic chemotherapy came to be identified as a means to gain improved potency from a drug, with minimum toxicity, through an antiangiogenic effect. Indeed, the concept has entered into the definition itself. Quoting Dr. Harold Burstein, “The definition of metronomic chemotherapy varies, but generally it refers to repetitive, low doses of chemotherapy drugs designed to minimize toxicity and target the endothelium or tumor stroma as opposed to targeting the tumor.” Of course, the original intent in the pioneering experiments with metronomic dosing was not to gain an antiangiogenic advantage, since that property would only be discovered later as an important consequence. Nevertheless, such a working definition has pervaded the literature, drawing focus to physiologic outcomes while begging the questions of just what metronomic dosing is in terms of dose scheduling, how alternative regimens should be compared, and most importantly, how it works.
In stark contrast to the up-front, maximum tolerated dosing (MTD)
strategy commonly employed in chemotherapy, metronomic dosing refers
to the spreading out of a dose over time so that dose is delivered in
small, regularly-spaced increments. For chemotherapy, this means
dividing the dose up into small equal increments across a
chemotherapeutic cycle, then repeating this pattern from one cycle to
the next. Strictly speaking, no particular treatment effect or outcome
is tied to the definition, although our group has uncovered some
hallmark quantitative properties of the strategy stemming from
sensitivity heterogeneity in the target population. In particular, for
radiation or chemotherapy treatments demonstrating log-linear kill
kinetics, we have established that any form of protracted dosing to an
asynchronous cell population would be asymptotically more suppressive
(in terms of the Malthusian ‘ultimate amplitude’ of
recovered long-term exponential growth) than an up-front acute dose of
the same magnitude [Hahnfeldt & Hlatky, 1996;
Hahnfeldt & Hlatky, 1998]. We have
followed up on this to show that, among protracted dosing schemes,
uniform dosing is optimal in this regard [Hahnfeldt, Folkman, & Hlatky, 2003]. As
we have shown, the effect has to do with the ongoing tendency of the
heterogeneous population to ‘resensitize’ as dosing
progresses. Because endothelium would be expected to be more efficient
in this regard than tumor cells, we rationalized that metronomic
dosing would naturally favor endothelial cell kill, thus be more
antiangiogenic, than its up-front MTD counterpart.
As these studies make clear, metronomic dosing is a departure from MTD in that the goal is no longer maximizing the probability of up-front population eradication, but about optimizing long-term tumor suppression. When eradication is an unlikely event, the alternative goal of chronic, long-term tumor suppression is not only reasonable, but the de facto goal of all follow-up treatments for recurrent or metastatic disease. However, despite the diametric differences in both approach and objective, efficacies of metronomic regimens are being held to the same stringent short-term response standards as MTD protocols. This has complicated the proper evaluation of these promising new strategies.
The purpose of the research in our group is to explore the totality of
features of metronomic dosing, and of dose response generally,
examining essential dependencies on dose sizes and timings in the
context of the dynamical tumor/host system. The belief is that, with
guiding principles in hand, more constructive exploitation of dose
response phenomena in treatment will be possible.
Workshop Hosted by CCSB:
- Workshop on Systems Biology of Tumor Metronomics, Tufts University Medford campus, July 17-20, 2012.
A strong body of work on the topic of therapeutic dose-response and heterogeneity has been published by researchers at CCSB (Click on title to go to manuscript abstract):
- Beheshti A, Wage J, McDonald JT, Lamont
C, Peluso M, Hahnfeldt P, Hlatky
L. Tumor-host signaling interaction reveals a systemic,
age-dependent splenic immune influence on tumor development.
Oncotarget. 2015 Nov 3;6(34):35419-32. Epub 2015 Oct 21. [Open Access]
- Benzekry S, Beheshti A, Hahnfeldt P, Hlatky
L. Capturing the driving role of tumor-host crosstalk in a
dynamical model of tumor growth. Bio-Protocol. 2015 Nov
- Girdhani S, Sachs R, Hlatky L. Biological effects of proton radiation: an update.
Radiat Prot Dosimetry. 2015 Sep;166(1-4):334-8. Epub 2015 Apr 20.
- Poleszczuk J, Hahnfeldt P, Enderling H. Therapeutic implications from sensitivity analysis of tumor
angiogenesis models. PLoS One. 2015 Mar
18;10(3):e0120007. PMCID: PMC4364928. [Open Access]
- Poleszczuk J, Hahnfeldt P, Enderling H. Evolution and phenotypic selection of
cancer stem cells. PLoS Comput Biol. 2015 Mar 5;11(3):e1004025. PMCID: PMC4351192. [Open Access]
- Radivoyevitch T, Siranart N, Hlatky L, Sachs
R. Stochastic process pharmacodynamics: dose timing in neonatal
gentamicin therapy as an example. AAPS J. 2015
Mar;17(2):447-56. Epub 2015 Feb 7. PMCID: PMC4365091.
- Benzekry S, Hahnfeldt P. Maximum tolerated dose
versus metronomic scheduling in treatment of metastatic cancers. J
Theor Biol. 2013 Oct 21; 335:235-44. Epub 2013 Jul 10.
- McGuire MF, Enderling H, Wallace DI, Batra J,
Jordan M, Kumar S, Panetta JC, Pasquier E. Formalizing an
integrative, multidisciplinary cancer therapy discovery
workflow. Cancer Res. 2013 Oct
15;73(20):6111-7. Epub 2013 Aug 16. PMCID: PMC4040396. [Open Access]
- Hahnfeldt P, Hlatky L, Klement GL. Center of Cancer Systems Biology Second Annual Workshop — Tumor
Metronomics: Timing and Dose Level Dynamics. Cancer Res. 2013 May
15; 73(10):2949-54. Epub 2013 Mar 14. PMCID: PMC3696500. [Open Access]
- Lignet F, Benzekry S, Wilson S, Billy F, Saut O, Tod M,
You B, Adda Berkane A, Kassour S, Wei MX, Grenier E, Ribba
B. Theoretical investigation of the efficacy of antiangiogenic drugs combined to chemotherapy in xenografted mice. J Theor
Biol. 2013 Mar 7; 320:86-99. Epub 2012 Dec 21.
- Benzekry S, André N, Benabdallah A, Ciccolini
J, Faivre C, Hubert F, Barbolosi D. Modeling the impact of
anticancer agents on metastatic spreading. Math Model Nat
Phenom. 2012 Jan; 7(1):306-36. Epub 25 Jan 2012.
- Hahnfeldt P, Folkman J, Hlatky L. Minimizing long-term tumor burden: the logic for metronomic
chemotherapeutic dosing and its antiangiogenic basis. J Theor
Biol. 2003 Feb 21; 220(4):545-54.
- Hahnfeldt P, Panigrahy D, Folkman J, Hlatky L. Tumor development under angiogenic signaling: a dynamical theory of
tumor growth, treatment response, and postvascular dormancy. Cancer
Res. 1999 Oct 1; 59(19):4770-5. [Open Access]
- Hahnfeldt P, Hlatky L. Cell resensitization during
protracted dosing of heterogeneous cell populations. Radiat Res. 1998 Dec; 150(6):681-7.
- Hahnfeldt P, Hlatky L. Resensitization due to redistribution of cells in the phases of the
cell cycle during arbitrary radiation protocols. Radiat Res. 1996