Abstract 1250: N-acetylcysteine pharmacokinetics and neuroprotection in a translational ovarian cancer model of cancer-related cognitive impairment.

Cancer Research · 2026-04-03

Abstract Background: Platinum-based chemotherapy is part of the standard of care for ovarian cancer treatment, yet more than 70% of patients develop cancer-related cognitive impairment (CRCI) during and after treatment. Cisplatin-induced CRCI is associated with alterations in plasma cytokines, mitochondrial dysfunction, and glutathione depletion. In an ovarian cancer xenograft rat model, the antioxidant N-acetylcysteine (NAC; 250 mg/kg, i.p.) prevented cisplatin-induced CRCI. To inform a Phase 1 study of oral NAC for CRCI prevention in ovarian cancer patients, we compared oral and i.p. NAC administration on brain and blood glutathione, plasma cytokines, circulating NAC levels, and cognition in female rats with or without ovarian cancer. Methods: Female RNU rats bearing SKOV3.ip1 xenografts received cisplatin (5 mg/kg, i.p.) biweekly for four cycles with or without NAC (250 mg/kg/day, i.p.) administered for five days during each cycle, 10 hours after cisplatin. Cognitive testing (novel object recognition, NOR) was performed 6-7 weeks after treatment completion. For NAC pharmacokinetic studies, 70 female non-tumor-bearing Sprague Dawley rats were randomized to vehicle, 250 mg/kg NAC i.p., and 159, 212, 265, 370, 476 mg/kg oral NAC, with or without cisplatin. Plasma, whole blood, and brain tissue were collected 2 hours after one cycle, and plasma NAC levels were quantified by mass spectrometry. Results: Ovarian tumor-bearing rats treated with or without cisplatin (OvT+VEH, OvT+CDDP) showed reduced NOR discrimination ratios (≤0.5) compared with non-tumor-bearing controls (NT+VEH, P=0.0207). NAC prevented cisplatin-induced impairments in the NOR task (OvT+CDDP vs. OvT+CDDP+NAC, P=0.0343). Cisplatin significantly reduced hippocampal and frontal cortex glutathione levels within 48 h, which was prevented by 250 mg/kg NAC, i.p. administration. NAC did not alter cisplatin’s anti-cancer activity or survival. Comparative analysis of plasma NAC levels after oral vs. i.p. administration is ongoing. Conclusions: NAC prevents cisplatin-induced CRCI in a clinically relevant ovarian cancer rodent model. Ongoing pharmacokinetic analyses will guide the design of a Phase 1 study of oral NAC in patients with ovarian cancer. Citation Format: Naomi Lomeli, Diana C. Pearre, Javier J. Lepe, Thomas H. Taylor, Daniela A. Bota. N-acetylcysteine pharmacokinetics and neuroprotection in a translational ovarian cancer model of cancer-related cognitive impairment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1250.

Abstract 382: Exploring the role of LONP1 in lon-traditional mechanisms of glioblastoma resistance.

Cancer Research · 2026-04-03

Abstract Temozolomide (TMZ) continues to serve as the frontline chemotherapy for glioblastoma (GBM), yet its long-term efficacy remains critically compromised due to the emergence of treatment resistance. While the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is the well-known contributor to TMZ resistance, clinical observations have shown that even tumors with minimal or silenced MGMT expression eventually acquire resistance, indicating additional, MGMT-independent pathways are involved. To investigate these alternative resistance mechanisms, we established two distinct glioblastoma models: TMZ-resistant (TR) cells characterized by high MGMT expression, and O6-Benzylguanine and TMZ-resistant (OTR) cells exhibiting low MGMT levels relative to parental controls. Our extensive analyses reveal a key function of the mitochondrial protease LonP1 in promoting TMZ resistance through metabolic adaptation. Both TR and OTR cell lines demonstrated significantly upregulated LonP1 expressions compared to parent glioblastoma cells, implicating elevated LonP1 as a central mediator in resistance development. Functional studies underscore that increased LonP1 expression contributes to a metabolic shift within resistant glioblastoma cells, transitioning from glycolytic metabolism towards enhanced oxidative phosphorylation (OXPHOS). This metabolic reprogramming equips resistant cells with improved capacity to sustain energetic and biosynthetic demands under TMZ-induced therapeutic stress. To validate LonP1’s causal role in resistance, we genetically overexpressed LonP1 in established glioma and patient-derived glioblastoma cell lines, resulting in robust acquisition of TMZ resistance. Conversely, downregulating LonP1 via targeted knockdown or pharmacologic inhibition restored sensitivity to TMZ, reducing cell viability and disrupting mitochondrial integrity. It is noteworthy that while our data firmly establish the necessity of LonP1 in maintaining TMZ resistance, the sufficiency of LonP1 overexpression to initiate resistance de novo in naïve tumor cells remains untested, as LonP1 knockout models were not leveraged for resistance induction. Collectively, our findings identify mitochondrial LonP1 protease as a promising target to overcome TMZ resistance in glioblastoma therapy. Inhibition of LonP1 activity could potentially reverse metabolic adaptations, thereby resensitizing resistant tumor cells to TMZ and improving treatment efficacy. This study provides a strong rationale for developing LonP1-targeted therapeutics as adjunctive agents in standard TMZ chemotherapy regimens, with the hope of delaying or reversing chemoresistance to improve clinical outcomes for glioblastoma patients. Citation Format: Shashi Jain, Dahlia A. Ordaz, Javier Lepe, Naomi Lomeli, James Pham, Bhaskar Das, Daniela A. Bota. Exploring the role of LONP1 in lon-traditional mechanisms of glioblastoma resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 382.

Abstract 5218: Leveraging a PARP inhibitor as neuroprotection against chemotherapy induced cognitive impairments

Cancer Research · 2026-04-03

Abstract Platinum-based (Pt) chemotherapies are lifesaving for many cancers, yet they induce persistent DNA damage and neuroinflammation that can profoundly alter cognitive function, collectively known as chemotherapy-induced cognitive impairments (CICI). The molecular drivers of these long-lasting effects remain mostly unknown, but symptoms include impaired concentration, memory deficits, and declines in speech and motor function this suggesting significant hippocampal vulnerability. Cisplatin, a widely used Pt agent causes extensive DNA crosslinking and robust proinflammatory signaling. Emerging evidence implicates poly (ADP-ribose) polymerase 1 (PARP1) in this process; when persistently activated by cisplatin-induced DNA damage- PARP1 drives metabolic dysfunction, inflammatory amplification, and impaired neuronal repair. PARP1 inhibitors have shown neuroprotective effects in other neurodegenerative disorders, reducing neuroinflammation and delaying functional decline. We hypothesized that excessive PARP1 activation contributes significantly to cisplatin-induced hippocampal dysfunction, and that targeted PARP inhibition could mitigate these neurotoxic cascades and preserve neuronal health. To determine whether the PARP inhibitor niraparib acts as a neuroprotective or rescue agent, we evaluated multiple treatment windows in vitro using mouse neural stem cells (MNSCs) from C57BL/6 mice. Cells were exposed to cisplatin (IC50: 0.4 µM) with niraparib (1 µM) administered pre-, post-, or concurrently. Niraparib significantly improved viability across all time points compared to cisplatin alone (p<0.0001). In primary hippocampal neurons (cisplatin IC50: 0.6 µM), combination treatment markedly increased PSD95 puncta and dendritic branching (p<0.0001), indicating preserved synaptic structure. To ensure that niraparib’s neuroprotection did not dimmish cisplatin’s anticancer efficacy, we tested the same low-dose combination in ID8/MOSEC and SKOV3.ip1 (IC50: 34.11 µM and IC50: 13.5 µM) ovarian cancer cell lines. No increase in viability was observed relative to cisplatin alone, confirming that niraparib did not interfere with cisplatin cytotoxicity. Together, these findings suggest that niraparib mitigates cisplatin-induced neurotoxicity while maintaining anti-cancer activity. Our next phase will evaluate niraparib alongside clinically relevant cisplatin dosing in C57BL/6 mice to assess cognitive outcomes in vivo. This works aims to clarify the mechanisms underlying CICI and identify strategies to improve quality of life and survivorship patients undergoing treatment. Citation Format: Dahlia A. Ordaz, Shashi Jain, Daniela A. Bota. Leveraging a PARP inhibitor as neuroprotection against chemotherapy induced cognitive impairments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5218.

Abstract 5217: Mast cell activation leads to cisplatin-induced peripheral neuropathy

Cancer Research · 2026-04-03

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a painful side effect of treating cancer with cisplatin. Cisplatin is a platinum-based chemotherapeutic that induces mast cell activation. Mast cells reside in close proximity of the epidermal layer, vasculature and nerve fibers in the skin. Tryptase and other noxious substances released by mast cells activate nociceptors via protease activated receptor -2 (PAR2) leading to pain. We hypothesized that cisplatin-induced mast cell activation leads to nerve injury and neuropathic pain. We used C57BL/6, wild-type (WT) and mast cell knockout (MC-KO) mice with a spontaneous c-kit "sash" mutation (KitW-sh) on a C57BL/6 background. Male and female mice were treated with cisplatin (i.p., 2.3 mg/kg/day), for 5 days of treatment followed by 5 days of saline (i.p.) for 2 cycles; or pre-treated with 100 mg/kg/day imatinib, an inhibitor of c-Kit and mast cell activation. Mechanical, cold, and thermal hyperalgesia were assessed at regular intervals. At day 18, cisplatin-treated mice showed a significant increase in mechanical hyperalgesia (p<0.001), cold hyperalgesia (p<0.05), and heat hyperalgesia (p<0.0001) compared to vehicle-treated mice. There were no changes in WT mice treated with imatinib or imatinib with cisplatin or in MC-KO mice treated with cisplatin for mechanical or thermal hyperalgesia, suggesting the involvement of mast cells in CIPN. Dorsal skin sections were co-stained with histone H3 (mast cell traps), FcεR1 (mast cell marker), and NF200 (nerve bundles). Cisplatin-treated mice showed activated mast cells surrounding nerve bundles, causing the expulsion of dense traps of citrullinated histones and podia extending into nerve fibers, causing nerve damage. The vehicle-treated mice showed intact, undisturbed thick nerve bundles without mast cell activation. Compared to vehicle, cisplatin-treated WT mice showed a significant increase in the number of non-degranulating and degranulating mast cells in dorsal (p<0.05) and toe skin (p<0.001, p<0.0001, respectively). We found a significant increase in cutaneous chymase (p<0.01), and tryptase (p<0.01), and plasma chymase (p<0.5), and tryptase (p<0.01) levels in cisplatin-treated compared to vehicle-treated WT mice. Human mast cells, HMC1.2, were incubated with 2, 5, and 10 µg/ml cisplatin or vehicle for 10 and 70 min, followed by analysis of chymase and tryptase in the conditioned medium. At the lowest dose of 2 µg/ml, cisplatin significantly stimulated the time-dependent release of chymase and tryptase compared to vehicle (p<0.01 for both). Together, our data show the novel phenomenon of mast cell traps upon cisplatin treatment leading to nerve injury, while tryptase released from mast cells may activate PAR-2 leading to the painful symptoms of CIPN. We speculate that the cotreatment of cisplatin with imatinib or other mast cell stabilizers such as cromolyn may ameliorate the painful symptoms of CIPN. Citation Format: Carolina Mireles, Donovan A. Argueta, Raghda Fouda, Sonal Joshi, Daniela A. Bota, Kalpna Gupta. Mast cell activation leads to cisplatin-induced peripheral neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5217.

MAGMAS Inhibition Enhances Temozolomide Efficacy in Chemotherapy-Resistant Glioblastoma Models

Cancer Research Communications · 2026-05-06

Glioblastoma (GBM, isocitrate dehydrogenase wildtype grade 4 astrocytoma) is the most aggressive and common brain tumor, characterized by increased proliferation, invasiveness, mitochondrial-dependent changes, and necrosis. GBM recurrence is universal despite the standard of care treatment with maximal surgical resection, radiation, and temozolomide (TMZ). Most patients relapse 6 to 9 months following initial diagnosis, and median survival after recurrence is less than a year. Therefore, effective therapeutic strategies are needed to overcome glioma resistance mechanisms and improve long-term outcomes for GBM patients. Mitochondria-associated granulocyte macrophage colony-stimulating factor molecule (MAGMAS, PAM16) is a nuclear-encoded mitochondrial protein subunit of the translocase of the inner membrane 23 (TIM23) complex that functions as an essential regulator of protein trafficking into the mitochondrial matrix. We previously demonstrated that MAGMAS is overexpressed in GBM, and that the small molecule MAGMAS inhibitor BT9 reduces mitochondrial respiration and is cytotoxic to glioma cells in vitro. Here, we investigated the role of MAGMAS in GBM biology and the effects of MAGMAS inhibition on TMZ-resistant glioma lines and patient-derived glioma stem-like cells (GSCs). We observed elevated PAM16 levels in recurrent GBM, chemoresistant glioma cells, and during metabolic switching processes. Concurrent treatment with BT9 and TMZ significantly increased cell death compared to either drug alone in all glioma lines, irrespective of their TMZ resistance status. Additionally, GBM cells constitutively expressing shPAM16 became sensitized to TMZ both in vitro and in vivo in an intracranial xenograft model. Our findings suggest that targeting MAGMAS holds promise as a novel, effective therapeutic strategy for GBM.

Abstract 556: Inhibition of mitochondrial protein MAGMAS increases sensitivity to standard of care treatment.

Cancer Research · 2026-04-03

Abstract Glioblastoma is a highly aggressive CNS cancer that affects 3 in 100,000 people every year in the U.S. The majority of patients experience tumor recurrence within the first year after initial diagnosis and after receiving standard of care treatment. GBM is characterized by its high mitotic index, capacity to invade other regions of the brain and modulate the tumor microenvironment (TME). Options are extremely limited for patients suffering from recurrent GBM as tumors become increasingly resistant to chemotherapy. Resistance to chemotherapy can be attributed to several factors that include DNA damage response (DDR), glioma stem cells (GSCs), TME, senescence mechanisms, and metabolic reprogramming. Mitochondria-associated granulocyte macrophage colony-stimulating factor molecule (MAGMAS), a mitochondria protein and subunit of the translocase of the inner membrane 23 (TIM23) complex, regulates protein trafficking into the mitochondria by recruiting DNAJC19 to the TIM23 complex. The present work was to investigate the role of MAGMAS in GBM tumor biology and mechanisms of resistance to TMZ. Computational analysis of MAGMAS/PAM16 expression levels from publicly available databases revealed that MAGMAS levels are significantly elevated in recurrent tumors and is positively correlated with the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) expression in primary patient tissues. We generated genetically modified glioma cells expressing shpam16 constructs and found that MAGMAS deficient glioma cells were sensitized to standard of care treatment that include TMZ, radiation and tumor treating fields (TTFs). Additionally, we discovered that silencing PAM16/MAGMAS reduced MGMT expression and reduced extracellular excretion of lactic acid. Interestingly, we also discovered that the cytokine IL7 and IL15 were significantly upregulated in MAGMAS KD cells. Taken together, our results demonstrate that MAGMAS plays an important role in chemotherapy resistance, metabolic reprogramming and potentially modulating the TME. By targeting MAGMAS, we can promote favorable conditions to enhance anti-tumor response using immunotherapy strategies in the future. Citation Format: Javier J. Lepe, Shashi Jain, Naomi Lomeli, Claire Chen, Bhaskar C. Das, Daniela A. Bota. Inhibition of mitochondrial protein MAGMAS increases sensitivity to standard of care treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 556.

Abstract 5216: Novel transdermal curcumin attenuates cisplatin induced neuropathy in a mouse model of breast cancer

Cancer Research · 2026-04-03

Abstract Cisplatin-induced neuropathy remains a major challenge to treat. Cisplatin disrupts mitochondrial homeostasis and increases reactive oxygen species (ROS) contributing to neuronal injury. We examined the ability of curcumin to prevent CIPN because it has antioxidant and neuroprotective properties. However, a major challenge is the reduced absorption and bioavailability of oral and systemically administered curcumin. To address this challenge, we used a novel transdermal curcumin (TDC) preparation which is bioavailable in the blood and central nervous system after topical application to the abdomen of mice. We used a transgenic mouse model of breast cancer (C3TAg) which shows the evolutionary spectrum of human breast cancer and its isotype control FVB/N mice. At ∼4 months of age female C3TAg mice develop palpable tumors and demonstrate mechanical, thermal and musculoskeletal hyperalgesia (P<0.0001 vs FVB/N). Mice were treated with vehicle or cisplatin (2.3 mg/kg/day i.p.) for two cycles of 5-days and 5 days of rest in the presence or absence of TDC/VAS-101 (0.1 mL) applied daily by rubbing on the abdomen of mice through the endpoint. Similar to cisplatin, TDC alone significantly reduced tumor weight (P<0.05 vs vehicle), and didn’t decrease the anti-tumor efficacy of cisplatin. By day 5, cisplatin induced significant mechanical and cold hyperalgesia in both strains (p<0.001 vs vehicle and BL), and musculoskeletal hyperalgesia at day 16 in C3TAg mice (P<0.001 vs BL; P<0.0001 vs vehicle). TDC co-treatment significantly attenuated cisplatin induced hyperalgesia (mechanical and cold, P<0.0001 vs cisplatin) and prevented musculoskeletal hyperalgesia (P<0.001 vs cisplatin). Notably, in C3TAg mice, TDC alone significantly decreased constitutive mechanical (P<0.001 vs vehicle; P<0.01 vs BL) and cold hyperalgesia (P<0.01 vs vehicle). These changes in hyperalgesia were accompanied by a significant reduction in phospho-p38 mitogen-activated protein kinase (MAPK) in dorsal root ganglion (DRG) neurons in C3TAg mice co-treated with TDC and cisplatin compared to cisplatin treatment (P<0.001) suggesting the activation of pain signaling. Furthermore, in primary DRG neurons and HT22 hippocampal neuronal cell line in culture, cisplatin elevated ROS and caused mitochondrial depolarization (P<0.0001; P<0.001 vs vehicle), which was prevented by TDC (P<0.0001). In HT22 neurons, cisplatin increased calcium release and lowered subsequent metabolic activity and viability (P<0.001 vs. vehicle), which were significantly inhibited by TDC (P<0.001), indicating that TDC targets the pain generating Ca2+ release from neuronal cells. In conclusion, TDC alleviates cancer- and chemotherapy-related hyperalgesia via inhibition of p38 MAPK and oxidative stress, while restoring mitochondrial function and limiting tumor growth. Thus, the novel TDC has a translational potential for preventing CIPN. Citation Format: Yugal Goel, Carolina Mireles, Dahlia Ordaz, Kendall O’Daniel, Kristen A. Peterson, Naomi Lomeli, Reina Lomeli, Daniela A. Bota, Joel Friedman, Kalpna Gupta. Novel transdermal curcumin attenuates cisplatin induced neuropathy in a mouse model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5216.

Dual targeting of the mitochondrial Lon peptidase 1 and the chymotrypsin-like proteasome activity as a potential therapeutic strategy in malignant astrocytoma models

Pharmacological Research · 2025-03-13 · 2 citations

Malignant astrocytomas are aggressive primary brain tumors characterized by extensive hypoxia-induced, mitochondria-dependent changes such as altered respiration, increased chymotrypsin-like (CT-L) proteasome activity, decreased apoptosis, drug resistance, stemness, and increased invasiveness. Mitochondrial Lon Peptidase 1 (LonP1) overexpression and increased CT-L proteasome activity are biomarkers of an aggressive high-grade phenotype and found to be associated with recurrence and poor patient survival. In preclinical models, small molecule agents targeting either LonP1 or the proteasome CT-L activity have anti-astrocytoma activity. Here, we present evidence that the dual inhibition of LonP1 and CT-L proteasome activity effectively induces ROS production, leading to apoptosis in malignant astrocytoma established cell lines and patient-derived glioma stem cell-like cultures. We also evaluated a novel small molecule, BT317, derived from the coumarinic compound 4 (CC4) using structure-activity modeling, which we found to inhibit both LonP1 and CT-L proteasome activity. Using gain- and loss-of-function genetic models, we discovered that LonP1 is both necessary and sufficient to drive BT317 drug sensitivity in established and patient-derived glioma stem-like cells by generating ROS and inducing apoptosis. In vitro, BT317 had activity as a single agent but, more importantly, enhanced synergy with the standard of care commonly used chemotherapeutic temozolomide (TMZ). In an orthotopic xenograft astrocytoma model, BT317 crossed the blood-brain barrier, showed selective activity at the tumor site, and demonstrated therapeutic efficacy as a single agent and combined with TMZ. BT317 defines an emerging class of LonP1 and CT-L inhibitors that exhibited promising anti-tumor activity and could be a potential candidate for malignant astrocytoma therapeutics. SIMPLE SUMMARY: Malignant astrocytoma patients have poor clinical outcomes, and novel treatments are needed to limit tumor recurrence and improve their overall survival. These tumors have a malignant phenotype mediated by altered mitochondrial metabolism, abnormal protein processing, and adaptation to hypoxia. We have previously published that astrocytomas are especially vulnerable to proteasome inhibitors as well as to inhibitors of the mitochondrial Lon Peptidase 1 (LonP1), but the effect of combining the two strategies has not been reported. Here, we present evidence that the dual inhibition of LonP1 and Chymotrypsin-like (CT-L) proteasome activity effectively induces cellular reactive oxygen species (ROS) production, leading to apoptosis in malignant astrocytoma established cell lines and patient-derived glioma stem cell-like cultures. We developed BT317, a small molecule dual inhibitor, which crosses the blood-brain barrier and shows strong synergy with the standard of care, temozolomide (TMZ), in the astrocytoma cell lines independent of their isocitrate dehydrogenase (IDH) profile and in an orthotopic glioma murine model. This preclinical study demonstrated the potential of dual LonP1 and CT-L proteasome inhibition as a novel therapeutic strategy for malignant astrocytoma and provides insight for future clinical translational studies alone or in combination with other chemotherapies.

A Digital Asthma Self-Management Program for Adults

JAMA Network Open · 2025-07-17 · 5 citations

Importance: Digital health technologies may improve asthma self-management, but evidence is limited in this area. Objective: To investigate the effect of a digital asthma self-management (DASM) program on asthma symptoms in adults. Design, Setting, and Participants: Patient-reported outcome results were reported from a randomized, pragmatic, parallel-arm, open-label, decentralized clinical trial. Adults with asthma were recruited via email, enrolled from October 29, 2020, through November 4, 2021, and were randomized to DASM or usual care (control). Participants completed study activities outside a clinical setting. Data were analyzed between October 13, 2023, and November 29, 2024. Intervention: The app-based DASM program provided tailored notifications, symptom logging, wearable device integration, and other tools. Main Outcomes and Measures: Change in the Asthma Control Test (ACT) was a primary outcome. The ACT is a validated measure of asthma control. Secondary outcomes included engagement and self-reported medication adherence. Results: Nine hundred and one participants were enrolled, with data available for 899 (639 [71.1%] female; mean [SD] age, 36.6 [10.5] years). For subgroup analyses, 195 participants (21.7%) were African American; 125 (13.9%), Hispanic or Latino; 680 (75.6%), commercially insured; and 219 (24.4%), Medicaid insured. Prespecified analyses of participants with uncontrolled asthma at baseline (n = 550) showed improvements after 12 months by 4.6 (95% CI, 4.1-5.2) ACT points among DASM participants (P < .001) and 1.8 (95% CI, 1.3-2.4) ACT points among controls (P < .001) (adjusted difference, 2.8 [95% CI, 2.0-3.6] points; P < .001). Race moderated this effect. At 12 months, the difference between arms in ACT change favored DASM over control by 1.0 (95% CI, -0.7 to 2.7) points (P = .26) for African American participants and 3.3 (95% CI, 2.4-4.2) points (P < .001) for participants not endorsing African American race (adjusted difference, -2.3 [95% CI, -4.2 to -0.4] points; P = .02 for interaction). Moderation was not observed by insurance (Medicaid vs commercial; adjusted difference, 1.0 [95% CI, -0.8 to 2.8] points; P = .18 for interaction) or ethnicity (Hispanic or Latino vs non-Hispanic; adjusted difference, 1.0 [95% CI, -1.3 to 3.3] points; P = .70 for interaction). Conclusions and Relevance: In this randomized clinical trial of DASM, improved asthma control was observed relative to usual care. Program adaptations may be appropriate to confer benefit throughout diverse populations. Trial Registration: ClinicalTrials.gov Identifier: NCT04609644.