Scalable Optimization Methods for Incorporating Spatiotemporal Fractionation into Intensity-Modulated Radiotherapy Planning

It has been recently shown that an additional therapeutic gain may be achieved if a radiotherapy plan is altered over the treatment course using a new treatment paradigm referred to in the literature as spatiotemporal fractionation. Because of the nonconvex and large-scale nature of the corresponding treatment plan optimization problem, the extent of the potential therapeutic gain that may be achieved from spatiotemporal fractionation has been investigated using stylized cancer cases to circumvent the arising computational challenges. This research aims at developing scalable optimization methods to obtain high-quality spatiotemporally fractionated plans with optimality bounds for clinical cancer cases. In particular, the treatment-planning problem is formulated as a quadratically constrained quadratic program and is solved to local optimality using a constraint-generation approach, in which each subproblem is solved using sequential linear/quadratic programming methods. To obtain optimality bounds, cutting-plane and column-generation methods are combined to solve the Lagrangian relaxation of the formulation. The performance of the developed methods are tested on deidentified clinical liver and prostate cancer cases. Results show that the proposed method is capable of achieving local-optimal spatiotemporally fractionated plans with an optimality gap of around 10%–12% for cancer cases tested in this study. Summary of Contribution: The design of spatiotemporally fractionated radiotherapy plans for clinical cancer cases gives rise to a class of nonconvex and large-scale quadratically constrained quadratic programming (QCQP) problems, the solution of which requires the development of efficient models and solution methods. To address the computational challenges posed by the large-scale and nonconvex nature of the problem, we employ large-scale optimization techniques to develop scalable solution methods that find local-optimal solutions along with optimality bounds. We test the performance of the proposed methods on deidentified clinical cancer cases. The proposed methods in this study can, in principle, be applied to solve other QCQP formulations, which commonly arise in several application domains, including graph theory, power systems, and signal processing.

Onset of action in placebo-controlled migraine attacks trials: A literature review and recommendation

Background Migraine patients want acute treatment to provide complete relief of the migraine attack within 30 minutes. Traditionally, “speed of onset of effect” is evaluated by estimating the time-point for first statistical separation of drug and placebo. The estimated onset of effect can be a few percent difference of patients being pain free in very large randomised, controlled trials. This difference, however, can be clinically irrelevant. Methods Placebo-controlled randomised, controlled trials with pain freedom results from 30 min to 2–4 hours were retrieved from the literature. For each time-point, the therapeutic gain (drug minus placebo) (TG) was calculated. Therapeutic gain for being pain free of 5% was chosen for the definition of “onset of action”, since this is approximately 1/3 of the 16% TG and 1/4 of 21% of TG for sumatriptan 50 mg and 100 mg, respectively. Results A total of 22 time-effect curves based on randomised, controlled trials were analysed. Based on the “onset of action” of 5% pain freedom, the evaluated drugs and administration forms can be classified as follows: i) Early time to onset, ≤30 min (three randomised, controlled trials); ii) medium time to onset, 60 min (nine randomised, controlled trials); iii) delayed time to onset, 90–120 min (10 randomised, controlled trials). Conclusion Only three non-oral administration forms with a triptan (subcutaneous sumatriptan and nasal zolmitriptan) resulted in an “onset of action” at ≥30 min; in the future, early onset of action should be a priority in the development of new drugs or new administration-forms for the treatment of acute migraine attacks.

Control of protein palmitoylation by regulating substrate recruitment to a zDHHC-protein acyltransferase

Although palmitoylation regulates numerous cellular processes, as yet efforts to manipulate this post-translational modification for therapeutic gain have proved unsuccessful. The Na-pump accessory sub-unit phospholemman (PLM) is palmitoylated by zDHHC5. Here, we show that PLM palmitoylation is facilitated by recruitment of the Na-pump α sub-unit to a specific site on zDHHC5 that contains a juxtamembrane amphipathic helix. Site-specific palmitoylation and GlcNAcylation of this helix increased binding between the Na-pump and zDHHC5, promoting PLM palmitoylation. In contrast, disruption of the zDHHC5-Na-pump interaction with a cell penetrating peptide reduced PLM palmitoylation. Our results suggest that by manipulating the recruitment of specific substrates to particular zDHHC-palmitoyl acyl transferases, the palmitoylation status of individual proteins can be selectively altered, thus opening the door to the development of molecular modulators of protein palmitoylation for the treatment of disease.

Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When?

Protease-activated receptors (PARs) are a family of four GPCRs with a variety of cellular functions, yet the only advanced clinical endeavours to target these receptors for therapeutic gain to date relates to the impairment of platelet function for anti-thrombotic therapy. The only approved PAR antagonist is the PAR1 inhibitor, vorapaxar—the sole anti-platelet drug against a new target approved in the past 20 years. However, there are two PARs on human platelets, PAR1 and PAR4, and more recent efforts have focused on the development of the first PAR4 antagonists, with first-in-class agents recently beginning clinical trial. Here, we review the rationale for this approach, outline the various modes of PAR4 inhibition, and speculate on the specific therapeutic potential of targeting PAR4 for the prevention of thrombotic conditions.

The CD73/Ado System—A New Player in RT Induced Adverse Late Effects

Radiotherapy (RT) is a central component of standard treatment for many cancer patients. RT alone or in multimodal treatment strategies has a documented contribution to enhanced local control and overall survival of cancer patients, and cancer cure. Clinical RT aims at maximizing tumor control, while minimizing the risk for RT-induced adverse late effects. However, acute and late toxicities of IR in normal tissues are still important biological barriers to successful RT: While curative RT may not be tolerable, sub-optimal tolerable RT doses will lead to fatal outcomes by local recurrence or metastatic disease, even when accepting adverse normal tissue effects that decrease the quality of life of irradiated cancer patients. Technical improvements in treatment planning and the increasing use of particle therapy have allowed for a more accurate delivery of IR to the tumor volume and have thereby helped to improve the safety profile of RT for many solid tumors. With these technical and physical strategies reaching their natural limits, current research for improving the therapeutic gain of RT focuses on innovative biological concepts that either selectively limit the adverse effects of RT in normal tissues without protecting the tumor or specifically increase the radiosensitivity of the tumor tissue without enhancing the risk of normal tissue complications. The biology-based optimization of RT requires the identification of biological factors that are linked to differential radiosensitivity of normal or tumor tissues, and are amenable to therapeutic targeting. Extracellular adenosine is an endogenous mediator critical to the maintenance of homeostasis in various tissues. Adenosine is either released from stressed or injured cells or generated from extracellular adenine nucleotides by the concerted action of the ectoenzymes ectoapyrase (CD39) and 5′ ectonucleotidase (NT5E, CD73) that catabolize ATP to adenosine. Recent work revealed a role of the immunoregulatory CD73/adenosine system in radiation-induced fibrotic disease in normal tissues suggesting a potential use as novel therapeutic target for normal tissue protection. The present review summarizes relevant findings on the pathologic roles of CD73 and adenosine in radiation-induced fibrosis in different organs (lung, skin, gut, and kidney) that have been obtained in preclinical models and proposes a refined model of radiation-induced normal tissue toxicity including the disease-promoting effects of radiation-induced activation of CD73/adenosine signaling in the irradiated tissue environment. However, expression and activity of the CD73/adenosine system in the tumor environment has also been linked to increased tumor growth and tumor immune escape, at least in preclinical models. Therefore, we will discuss the use of pharmacologic inhibition of CD73/adenosine-signaling as a promising strategy for improving the therapeutic gain of RT by targeting both, malignant tumor growth and adverse late effects of RT with a focus on fibrotic disease. The consideration of the therapeutic window is particularly important in view of the increasing use of RT in combination with various molecularly targeted agents and immunotherapy to enhance the tumor radiation response, as such combinations may result in increased or novel toxicities, as well as the increasing number of cancer survivors.

Targeting centrosome amplification, an Achilles' heel of cancer

Due to cell-cycle dysregulation, many cancer cells contain more than the normal compliment of centrosomes, a state referred to as centrosome amplification (CA). CA can drive oncogenic phenotypes and indeed can cause cancer in flies and mammals. However, cells have to actively manage CA, often by centrosome clustering, in order to divide. Thus, CA is also an Achilles' Heel of cancer cells. In recent years, there have been many important studies identifying proteins required for the management of CA and it has been demonstrated that disruption of some of these proteins can cause cancer-specific inhibition of cell growth. For certain targets therapeutically relevant interventions are being investigated, for example, small molecule inhibitors, although none are yet in clinical trials. As the field is now poised to move towards clinically relevant interventions, it is opportune to summarise the key work in targeting CA thus far, with particular emphasis on recent developments where small molecule or other strategies have been proposed. We also highlight the relatively unexplored paradigm of reversing CA, and thus its oncogenic effects, for therapeutic gain.

Health Canada’s Use of its Notice of Compliance With Conditions Drug Approval Policy: A Retrospective Cohort Analysis

Health Canada has developed its Notice of Compliance with conditions (NOC/c) policy to get promising new drugs for serious diseases to market faster than would be possible through its standard approval process. Companies can receive an NOC/c for a new drug or a new indication based on incomplete evidence in return for agreeing to conduct post-market studies. This paper investigates the additional therapeutic gain from drugs approved under this policy, the percent of drugs that have fulfilled their conditions, and the length of time for fulfillment. From the inception of the policy in 1998 to the end of 2017, 89 new drugs and new indications for existing drugs received an NOC/c. Therapeutic evaluations were available for 78 of the drugs, and 54 offered only minimal or no gains over existing products. Fifty NOC/c were fulfilled, 31 were not fulfilled, and 8 were withdrawn. The median time to fulfillment was 1,040 days. Twelve NOC/c took more than 5 years to fulfill their conditions. The unfulfilled NOC/c had been issued for a median of 1,161 days, and 10 had been issued more than 5 years. The value of the NOC/c policy to patients is uncertain.