Supplementary Figure 1 from RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer

Background: Although pencil beam scanning (PBS) is the most conformal method for proton beam therapy (PBT) delivery, it is unknown if outcomes differ compared to treatment with passive scatter/uniform scanning (PS/US). This analysis compares patient reported outcomes (PRO) changes following PBS and PS/US for prostate cancer (PC) in a prospective multicenter registry study. Methods: We evaluated PROs with the Expanded Prostate Cancer Index Composite (EPIC) instrument for men with localized PC enrolled in PCG 001-09 (NCT01255748). PROs were assessed at baseline and through 12 months of follow-up. We compared mean changes in EPIC scores, as well as the proportions of men experiencing a one- and two-fold minimally important difference (MID) in domain scores, between PBS and PS/US. Multivariate analyses (MVAs) were performed to further evaluate the association between proton modality and PRO changes. Results: Three-hundred-and-four men completed EPIC at baseline; 72 received PBS and 232 received PS/US. The average quality-of-life (QOL) declines from baseline through 12 months did not significantly differ between the two groups. The proportion of men reporting a 1-MID decline at 12 months for PBS and PS/US was 34.3% and 27.4%, respectively, for urinary QOL (P = 0.27); 40. 1% and 40.9% for bowel QOL (P = 0.36); and 30. 1% and 36.6% for sexual QOL (P = 0.94). Corresponding 2-MID declines for PBS and PS/US were observed in 26.9% and 13.2% of men for urinary QOL (P = 0.01), 35.3% and 29.1% for bowel QOL (P = 0.33); and 16.4% and 18.1% for sexual QOL (P = 0.76). The association between proton modality and 2-MID changes in urinary QOL at 12-months remained significant on MVA (P = 0.007). Conclusions: The results of this analysis show differences between PBS and PS/US with regards to two-fold MID changes in urinary function at 12 months, but no differences for average score declines over time. Future studies evaluating PRO measures between the two PBT modalities are warranted. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.

Introduction: Proton beam therapy (PBT) reduces normal organ dose compared to intensity-modulated radiation therapy (IMRT) for patients with major salivary gland tumors. It is not known whether this dosimetric advantage is clinically meaningful for reducing acute toxicity. Methods: We evaluated treatment parameters and acute toxicity outcomes of patients with major salivary gland cancers enrolled on the Proton Collaborative Group REG001-09 trial (NCT01255748). Results: One-hundred and five patients with a median age of 61 years were included. The majority had parotid (N = 90) versus submandibular gland (N = 15) tumors. The patients were treated across seven institutions in the United States between 2010 and 2017, most commonly in the postoperative setting (70.5%) although a minority were treated definitively (29.5%). Median PBT dose was 66.5 GyE in 33 fractions; only one patient was prescribed less than 50 GyE. Chemotherapy was given concurrently to 20%. Median follow-up was 14.3 months. Acute grade 2 or higher toxicity included nausea (1.5%), dysgeusia (4.8%), xerostomia (7.6%), mucositis (10.5%) and dysphagia (10.5%). Conclusions: PBT should be strongly considered when ipsilateral radiation therapy is indicated for major salivary gland cancer based on a considerably lower incidence of acute grade 2 or higher toxicity in this analysis compared to historical IMRT outcomes.

Background and purpose: Patient-level benefits of proton beam therapy (PBT) relative to photon therapy for prostate cancer (PC) continue to be the focus of debate. Although trials comparing the two modalities are underway, most are being conducted using "conventional" PBT (passive scattering/uniform scanning [PS/US]) rather than pencil beam scanning (PBS). The dosimetric benefits of PBS are well-known, but comparative data are limited. This analysis compares PBS toxicity rates with those of PS/US in a prospective multicenter registry. Methods: We evaluated acute/late gastrointestinal (GI) and genitourinary (GU) toxicity rates for men with low-to-intermediate risk PC enrolled in PCG 001-09. Acute toxicities with the two techniques were compared using chi(2) tests, and the cumulative incidence methods for late toxicity. Multivariable analyses (MVAs) for acute toxicity were performed using logistic regression, and cox proportional hazards models for late toxicity. Results: Patients were treated using PS/US (n = 1105) or PBS (n = 238). Acute grade >= 2 GI toxicity in PBS did not significantly differ from that with PS/US (2.9% and 2.1%, respectively; P = 0.47). Acute grade >= 2 GU toxicity was significantly higher with PBS (21.9% and 15.1%; P < 0.01). In MVA, PBS was significantly associated with increased acute grade >= 2 GU toxicity (RR = 1.57, p < 0.001). Late grade >= 2 GI and GU toxicities did not differ significantly between groups. Conclusions: This is the first multi-institutional comparative effectiveness evaluation of PBT techniques in PC. Differences in acute GU toxicity warrant further evaluation, and highlight the urgent need for prospective data using PBT. (C) 2019 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.

Proton therapy (PRT) is associated with reduced integral dose to normal brain tissue. While preliminary data is evolving on the efficacy of PRT for CNS tumors, little is known regarding which CNS patients are treated with PRT. We hypothesized that a large proportion of brain patients treated with PRT are young (pediatrics: <=18 years, young adults: 19-40 years) given the longer life expectancy over which they are at risk for CNS toxicity. We utilized the Proton Collaborative Group (PCG) registry, which prospectively follows patients across 8 academic and community PRT centers in the United States. Patients with spine tumors were excluded. The relative proportion of various histological classifications were evaluated by age group. Between 2009 and 2017, 1295 patients with diagnosis of a primary brain tumor were treated with PRT. Median age at PRT was 30.7 years (range, 0.73-92.2) with relatively equal sex distribution (52.5% male, 47.4% female). Most patients were pediatric (37.8%) or young adult (22.2%) and received PRT at initial diagnosis (67.3%) rather than at recurrence (32%). The frequency of tumor types treated varied by age group. Pediatric patients received PRT most frequently for embryonal tumors (28.2%), astrocytic tumors (19.8%), and ependymal tumors (19.4%). Among young adults, astrocytic tumors (27.4%), oligodendroglial/mixed gliomas (17.4%), and embryonal tumors (12.2%) were most frequently treated. Last, among adults >40 years, meningeal tumors (35.8%) were most commonly treated with PRT, followed by astrocytic tumors (27.1%) and oligodendroglial/mixed gliomas (11.4%). Primary brain tumor patients treated with PRT are young, with the majority treated for relatively favorable tumor types. This likely reflects the selection of patients that may derive the greatest benefit from reduction in brain dose. Additional studies including comparison of tumor types among CNS patients treated with photons are warranted.

Abstract Introduction The purpose of this study was to evaluate the dosimetric and radiobiological impact of intensity modulated proton therapy (IMPT) and RapidArc planning for high‐risk prostate cancer with seminal vesicles. Methods Ten high‐risk prostate cancer cases were included in this retrospective study. For each case, IMPT plans were generated using multiple field optimisation (MFO) technique (two fields) with XiO treatment planning system (TPS), whereas RapidArc plans were generated using double‐arc technique (two full arcs) with Eclipse TPS. IMPT and RapidArc plans were optimised for a total prescription dose of 79.2 Gy (relative biological effectiveness (RBE)) and 79.2 Gy, respectively, using identical dose–volume constraints. IMPT and RapidArc plans were then normalised such that at least 95% of the planning target volume (PTV) received the prescription dose. Results The mean and maximum PTV doses were comparable in IMPT plans (80.1 ± 0.3 Gy (RBE) and 82.6 ± 1.0 Gy (RBE) respectively) and RapidArc plans (80.3 ± 0.3 Gy and 82.8 ± 0.6 Gy respectively) with P = 0.088 and P = 0.499 respectively. The mean doses of the rectum and bladder were found to be significantly lower in IMPT plans (16.9 ± 5.8 Gy (RBE) and 17.5 ± 5.4 Gy (RBE) respectively) when compared to RapidArc plans (41.9 ± 5.7 Gy and 32.5 ± 7.8 Gy respectively) with P < 0.000 and P < 0.000 respectively. For the rectum, IMPT produced lower V30 (21.0 ± 9.6% vs. 68.5 ± 10.0%; P < 0.000), V50 (14.3 ± 5.8% vs. 45.0 ± 10.0%; P < 0.000) and V70 (6.9 ± 3.4% vs. 12.8 ± 3.6%; P < 0.000) compared to RapidArc. For the bladder, IMPT produced lower V30 (23.2 ± 7.0% vs. 50.9 ± 15.6%; P < 0.000) and V50 (16.6 ± 5.4% vs. 25.1 ± 9.6%; P = 0.001), but similar V70 (9.7 ± 3.5% vs. 10.5 ± 4.2%; P = 0.111) compared to RapidArc. RapidArc produced lower mean dose for both the right femoral head (19.5 ± 4.2 Gy vs. 27.4 ± 4.5 Gy (RBE); P < 0.000) and left femoral head (18.0 ± 4.3 Gy vs. 28.0 ± 5.6 Gy (RBE); P < 0.000). Both IMPT and RapidArc produced comparable bladder normal tissue complication probability (NTCP) (0.6 ± 0.2% vs. 0.5 ± 0.2%; P = 0.152). The rectal NTCP was found to be lower using IMPT (0.8 ± 0.7%) than using RapidArc (1.7 ± 0.7%) with P < 0.000. Conclusion Both IMPT and RapidArc techniques provided comparable mean and maximum PTV doses. For the rectum, IMPT produced better dosimetric results in the low‐, medium‐ and high‐dose regions and lower NTCP compared to RapidArc. For the bladder, the NTCP and dosimetric results in the high‐dose region were comparable in both sets of plans, whereas IMPT produced better dosimetric results in the low‐ and medium‐dose regions.

Proton therapy patterns-of-care and early outcomes for Hodgkin lymphoma: results from the Proton Collaborative Group Registry

Background. Proton beam therapy (PBT) for prostate cancer generally involves the use of two lateral beams that transverse the hips. In patients with hip replacements or a previously irradiated hip, this arrangement is contraindicated. The use of non-lateral beams is possible, but not well described. Here we report a multi-institutional experience for patients treated with at least one non-lateral proton beam for prostate cancer.Material and methods. Between 2010 and 2014, 20 patients with organ-confined prostate cancer and a history of hip prosthesis underwent proton therapy utilizing at least one anterior oblique beam (defined as between 10 degrees and 85 degrees from vertical) at one of three proton centers.Results. The median follow-up was 6.4 months. No patients have developed PSA failure or distant metastases. The median planning target volume (PTV) D95 was 79.2 Gy (RBE) (range 69.7-79.9). The median rectal V70 was 9.2% (2.5-15.4). The median bladder V50, V80, and mean dose were 12.4% (3.7-27.1), 3.5 cm(3) (0-7.1), and 14.9 Gy (RBE) (4.6-37.8), respectively. The median contralateral femur head V45 and max dose were 0.01 cm(3) (0-16.6) and 43.7 Gy (RBE) (15.6-52.5), respectively. The incidence of acute Grade 2 urinary toxicity was 40%. There were no Grade >= 3 urinary toxicities. There was one patient who developed late Grade 2 rectal proctitis, with no other cases of acute or late >= Grade 2 gastrointestinal toxicity. Grade 2 erectile dysfunction occurred in two patients (11.1%). Mild hip pain was experienced by five patients (25%). There were no cases of hip fracture.Conclusion. PBT for prostate cancer utilizing anterior oblique beam trajectories is feasible with favorable dosimetry and acceptable toxicity. Further follow-up is needed to assess for long-term outcomes and toxicities.

The purpose of this study is to compare the dosimetric results between the uniform scanning proton therapy (USPT) and intensity modulated proton therapy (IMPT) plans for the prostate cancer in patients with a unilateral metallic hip prosthesis. Five prostate cancer cases with left (n = 3) and right (n = 2) metallic hip prostheses were included in this retrospective study. For each case, the USPT and IMPT plans were generated using two anterior-oblique beams and one lateral beam for a total dose of 79.2 Gy(RBE) to be delivered in 44 fractions. For a given case, the beam parameters, dose prescription, and delivery schema in the IMPT plan were kept identical to the ones in the USPT plan. The IMPT and USPT plans were compared for various dosimetric parameters. The mean dose to the target volume was comparable. Both the IMPT and USPT techniques achieved the target coverage goals. Dose homogeneity was found to be similar in the IMPT and USPT plans. For both the rectum and bladder, the IMPT plans produced favorable dosimetric results in the low-, medium-, and high-dose regions when compared to the USPT plans. For the high dose regions, the rectal V 70 was lower in the IMPT plans by about 3.89 cc when compared to the one in the USPT plans. The rectal V 80 in the IMPT plans (1.10 cc) was almost half than the one in the USPT plans (2.39 cc). In comparison to the USPT plans, the mean dose to the rectum, bladder, and femoral head were lower in the IMPT plans by about 8.91%, 4.15%, and 41.09%, respectively. Based on the preliminary results of five cases presented in this study, the IMPT plans provided slightly better dosimetric results compared to the USPT plans, especially in sparing the rectum and bladder in the low-, medium-, and high-dose regions, for the treatment of the prostate cancer in patients with a unilateral metallic hip prosthesis. Future studies need to address the impact of the setup uncertainties and intra-fraction prostate motion in the IMPT planning of the prostate cancer patients with prosthetic hip replacements.

Purpose: The purpose of this study is to evaluate the dosimetric effect of rotational setup errors on the synchronous bi-lateral lung cancer plans generated by the intensity modulated proton therapy (IMPT) technique. Methods: The original IMPT plans were generated in for the left planning target volume (PTV) and right PTV of the left lung and right lung, respectively. Each plan was generated using two beams (lateral and posterior-anterior) with an isocenter placed at the center of the corresponding PTV. The IMPT plans were optimized for a total dose of 74 Gy[RBE] prescribed to each PTV with 2 Gy(RBE) per fraction. Original plans were recalculated by introducing simulated rotational errors. For each PTV, 18 rotational plans (±1⁰, ±2⁰, and ±3⁰) for each of the yaw, roll, and pitch rotations were generated. Results: Rotational errors caused the reduction in the clinical target volume (CTV) and PTV coverage in new rotational IMPT plans when compared to the original IMPT lung plans. The CTV D99 was reduced by up to 13.3%, 9.1%, and 5.9% for the yaw (+3⁰), roll (-3⁰), and pitch (+3⁰), respectively. The PTV D95 was reduced by up to 8.7%, 7.3%, and 4.6% for the yaw (+3⁰), roll (-3⁰), and pitch (+3⁰), respectively. The PTV V100 showed the highest deviation with a reduction of dose coverage by up to 40.1%, 31.8%, and 33.9% for the yaw (-3⁰), roll (-3⁰), and pitch (+3⁰) respectively. Conclusion: The rotational setup errors with magnitude of ≥2⁰ can produce a significant loss of dose coverage to the target volume in the IMPT of a synchronous bi-lateral lung cancer. The yaw had the most severe impact on the dosimetric results when compared to other two rotational errors (roll and pitch).

Purpose: Failure mode and effects analysis (FMEA) is a widely used tool to evaluate safety or reliability in conventional photon radiation therapy. However, reports about FMEA application in proton therapy are scarce. The purpose of this study is to apply FMEA in safety improvement of proton treatment planning at their center. Methods: The authors performed an FMEA analysis of their proton therapy treatment planning process using uniform scanning proton beams. The authors identified possible failure modes in various planning processes, including image fusion, contouring, beam arrangement, dose calculation, plan export, documents, billing, and so on. For each error, the authors estimated the frequency of occurrence, the likelihood of being undetected, and the severity of the error if it went undetected and calculated the risk priority number (RPN). The FMEA results were used to design their quality management program. In addition, the authors created a database to track the identified dosimetric errors. Periodically, the authors reevaluated the risk of errors by reviewing the internal error database and improved their quality assurance program as needed. Results: In total, the authors identified over 36 possible treatment planning related failure modes and estimated the associated occurrence, detectability, and severity to calculate the overall risk priority number. Based on the FMEA, the authors implemented various safety improvement procedures into their practice, such as education, peer review, and automatic check tools. The ongoing error tracking database provided realistic data on the frequency of occurrence with which to reevaluate the RPNs for various failure modes. Conclusions: The FMEA technique provides a systematic method for identifying and evaluating potential errors in proton treatment planning before they result in an error in patient dose delivery. The application of FMEA framework and the implementation of an ongoing error tracking system at their clinic have proven to be useful in error reduction in proton treatment planning, thus improving the effectiveness and safety of proton therapy.

The main purposes of this study were to 1) investigate the dosimetric quality of uniform scanning proton therapy planning (USPT) for prostate cancer patients with a metal hip prosthesis, and 2) compare the dosimetric results of USPT with that of volumetric-modulated arc therapy (VMAT). Proton plans for prostate cancer (four cases) were generated in XiO treatment planning system (TPS). The beam arrangement in each proton plan consisted of three fields (two oblique fields and one lateral or slightly angled field), and the proton beams passing through a metal hip prosthesis was avoided. Dose calculations in proton plans were performed using the pencil beam algorithm. From each proton plan, planning target volume (PTV) coverage value (i.e., relative volume of the PTV receiving the prescription dose of 79.2 CGE) was recorded. The VMAT prostate planning was done using two arcs in the Eclipse TPS utilizing 6 MV X-rays, and beam entrance through metallic hip prosthesis was avoided. Dose computation in the VMAT plans was done using anisotropic analytical algorithm, and calculated VMAT plans were then normalized such that the PTV coverage in the VMAT plan was the same as in the proton plan of the corresponding case. The dose-volume histograms of calculated treatment plans were used to evaluate the dosimetric quality of USPT and VMAT. In comparison to the proton plans, on average, the maximum and mean doses to the PTV were higher in the VMAT plans by 1.4% and 0.5%, respectively, whereas the minimum PTV dose was lower in the VMAT plans by 3.4%. The proton plans had lower (or better) average homogeneity index (HI) of 0.03 compared to the one for VMAT (HI = 0.04). The relative rectal volume exposed to radiation was lower in the proton plan, with an average absolute difference ranging from 0.1% to 32.6%. In contrast, using proton planning, the relative bladder volume exposed to radiation was higher at high-dose region with an average absolute difference ranging from 0.4% to 0.8%, and lower at low-and medium-dose regions with an average absolute difference ranging from 2.7% to 10.1%. The average mean dose to the rectum and bladder was lower in the proton plans by 45.1% and 22.0%, respectively, whereas the mean dose to femoral head was lower in VMAT plans by an average difference of 79.6%. In comparison to the VMAT, the proton planning produced lower equivalent uniform dose (EUD) for the rectum (43.7 CGE vs. 51.4 Gy) and higher EUD for the femoral head (16.7 CGE vs. 9.5 Gy), whereas both the VMAT and proton planning produced comparable EUDs for the prostate tumor (76.2 CGE vs. 76.8 Gy) and bladder (50.3 CGE vs. 51.1 Gy). The results presented in this study show that the combination of lateral and oblique fields in USPT planning could potentially provide dosimetric advantage over the VMAT for prostate cancer involving a metallic hip prosthesis.

The main purpose of this study was to perform a treatment planning study for lung cancer comparing 2-field (2F) versus 3-field (3F) techniques in uniform scanning proton therapy (USPT). Ten clinically approved lung cancer treatment plans delivered using USPT at our proton center were included in this retrospective study. All 10 lung cases included 4D computed tomography (CT) simulation. The delineation of target volumes was done based on the maximum intensity projection (MIP) images. Both the 3F and 2F treatment plans were generated for the total dose of 74 cobalt-gray-equivalent (CGE) with a daily dose of 2 CGE. 3F plan was generated by adding an extra beam in the 2F plan. Various dosimetric parameters between 2F and 3F plans were evaluated. 3F plans produced better target coverage and conformality as well as lower mean dose to the lung, with absolute difference between 3F and 2F plans within 2%. In contrast, the addition of third beam led to increase of low-dose regions (V20 and V5) in the lung in 3F plans compared to the ones in 2F plans with absolute difference within 2%. Maximum dose to the spinal cord was lower in 2F plans. Mean dose to the heart and esophagus were comparable in both 3F and 2F plans. In conclusion, the 3F technique in USPT produced better target coverage and conformality, but increased the low-dose regions in the lung when compared to 2F technique.

Purpose: The main objective of this study was to compare the dosimetric quality of volumetric modulated arc therapy (VMAT) with that of proton therapy for high-risk prostate cancer. Patients and Materials: Twelve patients with high-risk prostate cancer previously treated with uniform scanning proton therapy (USPT) were included in this study. Proton planning was done using the XiO treatment planning system (TPS) with two 1800 parallel-opposed lateral fields. The VMAT planning was done using the RapidArc technique with two arcs in the Eclipse TPS. The VMAT and proton plans were calculated using the anisotropic analytical algorithm and pencil-beam algorithm, respectively. The calculated VMAT and proton plans were then normalized so that at least 95% of the planning target volume (PTV) received the prescription dose. The dosimetric evaluation was performed by comparing the physical dose-volume parameters, which were obtained from the VMAT and proton plans. Results: The average difference in the PTV ...

Anionic phospholipids, principally phosphatidylserine (PS), become exposed on the external surface of vascular endothelial cells in tumors, providing an excellent marker for tumor vascular targeting. Binding of antibodies targeting PS on the tumor endothelial cells and tumors recruits immune cells and engages the immune system to destroy tumor vasculature. The antibodies also enhance anti-tumor immunity by blocking the immunosuppressive action of PS. A chimeric anti-PS antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in Phase II trials. We have engineered mutations in the Fc region of fully human PS-targeting antibody PGN635 that enhance the interaction with FcRgammaIIIa and have characterized their ability to exert anti-tumor effects through various mechanisms, including ADCC and cytokine induction. Mutations that enhance Fc-FcR interaction of PS targeting antibodies enhance production of pro-inflammatory chemokines such as MCP-1 (CCL2), MIP-1alpha (CCL3) and MIP-1beta (CCL4). In addition, the same Fc mutations enhance ADCC of PS expressing tumor targets. Our data indicate that improvement of multiple immune effector functions via enhanced interaction of Fc-FcR interaction of PS-targeting antibodies may improve the treatment of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2510. doi:1538-7445.AM2012-2510

Abstract The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncology therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The structural, pharmacologic, and pharmacokinetic properties of RDEA119/BAY 869766, an allosteric MEK inhibitor, are presented. RDEA119/BAY 869766 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes. This compound is highly efficacious at inhibiting cell proliferation in several tumor cell lines in vitro. In vivo, RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system–related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, RDEA119/BAY 869766 has the potential for use as a once- or twice-daily oral treatment for cancer. RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clinical development because of its potency and favorable pharmacokinetic profile. [Cancer Res 2009;69(17):6839–47]

Purpose: Ulcerative colitis (UC) is a chronic relapsing immune mediated disorder characterized by diffuse mucosal inflammation limited to the colon. Various components of the immune system including secreted inflammatory mediators are implicated in the pathogenesis of the disease. Mitogen-activated protein kinase (MEK) signaling pathways are known to play an important role in the development of inflammatory diseases via the regulation of cytokine production. This study was designed to assess the effect of RDEA119, a potent highly selective inhibitor of MEK1/2 signaling pathways in DSS-induced chronic UC in mice. Methods: Male C57BL/6 mice were used in two separate studies. Study 1: Mice were exposed to two cycles of DSS (1% DSS in drinking water). Mice were then dosed orally (QD) with either 1:9 cremophor-saline (C-S; vehicle) or RDEA119 (0.3, 1, or 3 mg/kg) for 8 consecutive days, and euthanized on day 9. Positive control mice received the anti-TNF-alpha antibody remicade (10 micrograms/g body weight every over day; SC) and examined as above. Study 2: Conducted as above with the dosing period extended to 14 days. Mice were euthanized and examined on day 15 post-dosing initiation. Colonic tissues were harvested and the effectiveness of RDEA119 in achieving and maintaining the therapeutic goal of mucosal healing assessed. Disease activity index (DAI) and tissue myeloperoxidase (MPO) activity were assessed at the end of study 2. Results: (1) Compared to C-S (7.4 ± 0.9), RDEA119 at 3 mg/kg (4.4 ± 0.7) significantly reduced the histological damage score of colon by 41% as illustrated by the well-preserved mucosal architecture and reduced tissue infiltration. Remicade (5.6 ± 1.0) reduced the colonic damage by 24% only. (2) Compared to C-S (6.4 ± 1.4), RDEA119 at 1 (3.4 ± 0.4) and 3 (2.6 ± 0.5) mg/kg significantly reduced the histological damage score by 47% and 59% respectively. The magnitude of colonic damage reduction was of 22% in mice treated with remicade. Increased DAI in C-S (0.7 ± 0.1) was significantly reduced in mice treated with RDEA119 at 1 (0.1±0.1; 86% reduction) and 3 (0.3 ± 0.1; 57% reduction) mg/kg. Compared to absolute DSS control “ADSSC” (0.9 ± 0.2), RDEA119 at 1 and 3 mg/kg reduced the DAI by 89% and 67% respectively. Increased MPO activity in colonic tissues from ADSSC (0.323±0.05 U/mg tissue “UMT”) was also reduced by RDEA119 at 1 (0.201 ± 0.06 UMT; 40% reduction) and 3 (0.162±0.03 UMT; 52% reduction) mg/kg. Remicade (0.197±0.03 UMT) reduced MPO activity by 41%. Conclusion: RDEA119 (0.3–3 mg/kg; PO) improves chronic murine DSS colitis. Blockade of MEK1/2 signaling pathways is a suitable strategy to treat UC as well as Crohn's disease. RDEA119 is considered a promising investigational therapy for inflammatory diseases.