Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537S ESR1 Mutant Breast Cancer Cells.

Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ERα breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29's activities in breast cancer cells harboring Y537S ERα. RNA sequencing in cells treated with T6I-29 reveals a neomorphic downregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER+ breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER+ breast cancers.

Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537S ESR1 Mutant Breast Cancer Cells.

Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ERα breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29's activities in breast cancer cells harboring Y537S ERα. RNA sequencing in cells treated with T6I-29 reveals a neomorphic downregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER+ breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER+ breast cancers.

SU-E-T-616: Efficacy of Biological Dose Painting for Head and Neck Cancer.

PURPOSE: Study the feasibility and planning robustness of a novel biological dose painting approach prescribing biological effect instead of dose. METHODS: Prescribed'effect maps' were generated using models relating FMISO-PET tracer uptake to hypoxia reduction factors (HRF). HRFs decrease the LQ-model radio response parameters a and ß and therefore the delivered biological effect. The model is driven by four parameters (m, K, p50, Imax), whose values have been determined through a comprehensive literature search. A planning study on ten previously treated patients with oropharyngeal cancer was conducted. Dose-painted plans were generated with the KonRad inverse planning system (DKFZ, Heidelberg). Simulated FMISO-PET images were generated by defining clinically relevant hypoxic sub-volumes within the GTV. Tracer uptake values were derived from various PET imaging studies for head and neck cancer. Each treatment plan was developed in four steps: 1) Simulate hypoxia tracer distribution in GTV. 2) Prescribe biological effect. 3) Optimize dose-painted plan under the same normal tissue constraints of the nominal clinical plan. 4) Conduct robustness analysis by evaluation of the dose-painted plan for 27 parameters combinations of K, m, p50 (mean ± 1SD). RESULTS: The predicted biological effect of clinical plans under normoxic conditions overestimates the delivered effect due to decreased radio-sensitivity in hypoxic tumours. Biological dose painting compensates for hypoxia by delivering a higher dose to hypoxic sub-volumes while still maintaining all critical structure dose limits. Model parameter uncertainties clearly affect robustness. The high uncertainty on p50 (pO2 for which tracer concentration is half of maximum uptake) was found to cause the largest variations in the delivered biological effect. CONCLUSIONS: Clinically acceptable dose-painted plans can be generated without sacrificing the normal tissue constraints. Planning robustness suffers from the high uncertainty on the p50 value. Improved methods to determine the model parameters would be desirable. Financial support provided by Ryerson University, Toronto, Ontario, Canada.

The robustness of cognitively simple judgment in ecologies of Prisoner's Dilemma games.

Various authors have pointed to the fitness advantage from a capacity to recognize others' intentions in prisoner's dilemma games, yet cognitive mechanisms supporting such perceptiveness might be no more efficient than the simple and presumably inexpensive rule to 'assume that potential partners have the same behavioral intentions as yourself.' Laboratory findings have shown that this projecting heuristic can support the evolution of cooperative behavior absent perceptiveness, but that rule might be vulnerable to invasion by perceptive mutations. This paper shows that perceptive mutants are more likely to destroy an entire ecology of projectors (that would otherwise survive and prosper) than to successfully invade it, while projecting mutants have considerable success invading a population of perceptives. Mutant projectors' success happens when a cooperative ecology is created for them by the initial success of perceptive cooperators; within such an ecology, cooperative projectors have a competitive advantage over cooperative perceptives. Critical parameters are (1) the incidence of cooperativeness in the population and (2) the price of perceptiveness.

[Cytomegalovirus hyperimmunoglobulin prophylaxis following kidney transplantation. Results of a prospective randomized study]. / CMV-Hyperimmunoglobulinprophylaxe nach Nierentransplantation. Ergebnisse einer prospektiv randomisierten Studie.

The effectiveness of preventing cytomegalovirus (CMV) infections by administering CMV hyperimmunoglobulin was evaluated in a prospective randomized trial. The patients in the treatment group (n = 50) had intravenous infusions of 2 ml/kg bodyweight of CMV-Polyglobin at three-week intervals, up to day 105 after kidney transplantation. The 50 patients in the control group received no infusions. There was no significant difference between the treatment and control groups in transplant survival or patients survival rates. But the number of symptomatic CMV infections was higher in the control (n = 11) than the treatment group (n = 5). There were also significantly fewer symptomatic herpes-simplex infections in the treatment (n = 6) than in the control group (n = 25). It is concluded from these results that prophylaxis with CMV hyperimmunoglobulin should be undertaken either selectively or for shorter periods than those chosen for the reported trial.

[Cytomegalovirus infections after kidney transplantation and passive immunization]. / Zytomegalievirusinfektionen nach Nierentransplantationen und passive Immunisierung.

Cytomegalovirus infection after renal transplantation impairs the survival rate of patient and graft. An incidence of 24 to 92% of CMV infections after renal transplantation is reported, but only 15 to 77% of these patients show clinical symptoms. Contaminated donor organs, blood transfusions and reactivation by immunosuppression are the main causes of this infection. Active immunisation cannot prevent the reactivation of the infection, but also antiviral agents can hardly influence the course of the disease. Passive immunisation showed promising effects in bone-marrow transplantation and is now also tried in renal transplantation. The first results of a randomized study do not allow a final conclusion, but show less clinical symptomatic CMV infections, and statistically significant less herpes simplex infections in the group receiving anti CMV IgG prophylaxis.