Systematic engineering of TROP2-targeted CAR T-cell therapy overcomes resistance pathways in solid tumors.

Antibody-based therapies have revolutionized cancer treatment but have several limitations. These include: down-regulation of the target antigen; mutation of the target epitope; or in the case of antibody drug conjugates (ADCs), resistance to the chemotherapy warhead. Since TROP2-targeted therapy with ADCs yields responses in TROP2+ solid tumors but lacks the durability observed with other immunotherapy-based approaches, we developed novel TROP2-targeting chimeric antigen receptor (CAR) T cells as an alternative.

Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors.

Small-cell lung cancers (SCLCs) contain near-universal loss-of-function mutations in RB1 and TP53, compromising the G1-S checkpoint and leading to dysregulated E2F activity. Other cancers similarly disrupt the G1-S checkpoint through loss of CDKN2A or amplification of cyclin D or cyclin E, also resulting in excessive E2F activity. Although E2F activation is essential for cell cycle progression, hyperactivation promotes apoptosis, presenting a therapeutic vulnerability.

Eradicating Drug Tolerant Persister Cells in EGFR-Mutated Non-Small Cell Lung Cancer by Targeting TROP2 with CAR-T cellular therapy.

EGFR tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes for EGFR-mutated non-small cell lung cancer (NSCLC) patients, but relapse frequently occurs due to drug tolerant persister (DTP) cells that can evolve and develop diverse mechanisms of drug resistance. In samples from patients with EGFR-mutated NSCLC treated with EGFR-TKIs in the neoadjuvant setting, we observed enriched expression of the cell surface protein TROP2, a target of clinically active antibody drug conjugates (ADCs). We confirmed these findings across multiple EGFR-mutated NSCLC cell line and patient-derived xenograft models treated with osimertinib in vivo.

Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity.

Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC).

Topical Calcipotriol Plus Imiquimod Immunotherapy for Nonkeratinocyte Skin Cancers.

Nonkeratinocyte cutaneous malignancies, including breast cancer cutaneous metastasis and melanoma in situ, are often poor surgical candidates. Imiquimod (IMQ), a toll-like receptor 7 agonist that activates innate immunity in the skin, is used to treat these cutaneous malignancies. However, IMQ's modest effect on the activation of adaptive immunity limits its efficacy as a monotherapy.

Cotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer.

Despite the success of KRAS G12C inhibitors in non-small cell lung cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to cotarget RAS and mTOR pathways; however, toxicity due to broad mTOR inhibition has limited its utility. Therefore, we sought to develop a more refined means of targeting cap-dependent translation and identifying the most therapeutically important eukaryotic initiation factor 4F complex-translated (eIF4F-translated) targets.

EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for -mutant non-small cell lung cancers (NSCLC). However, most patients develop acquired drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in -mutant NSCLC.

Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of -mutant lung cancer.

The clinical efficacy of epidermal growth factor receptor (EGFR)–targeted therapy in -mutant non–small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor () proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent mutation and amplification are historically thought to be codependent on the activation of both oncogenes.

Acute pharmacological degradation of Helios destabilizes regulatory T cells.

The zinc-finger transcription factor Helios is critical for maintaining the identity, anergic phenotype and suppressive activity of regulatory T (T) cells. While it is an attractive target to enhance the efficacy of currently approved immunotherapies, no existing approaches can directly modulate Helios activity or abundance. Here, we report the structure-guided development of small molecules that recruit the E3 ubiquitin ligase substrate receptor cereblon to Helios, thereby promoting its degradation.

Intense Arm Rehabilitation Therapy Improves the Modified Rankin Scale Score: Association Between Gains in Impairment and Function.

Objective: To evaluate the effect of intensive rehabilitation on the modified Rankin Scale (mRS), a measure of activities limitation commonly used in acute stroke studies, and to define the specific changes in body structure/function (motor impairment) most related to mRS gains.

Methods: Patients were enrolled >90 days poststroke. Each was evaluated before and 30 days after a 6-week course of daily rehabilitation targeting the arm.

Reduction in Human Epidermal Langerhans Cells with Age Is Associated with Decline in CXCL14-Mediated Recruitment of CD14 Monocytes.

The skin provides the first line of physical and immunological defense against environmental insults. However, the age-related changes in the immune function of human skin are unclear. Here, we investigated the age-related changes in epidermal Langerhans cells (LCs), which play a sentinel role in the initiation of the immune responses in the skin.

Immunity to commensal papillomaviruses protects against skin cancer.

Immunosuppression increases the risk of cancers that are associated with viral infection. In particular, the risk of squamous cell carcinoma of the skin-which has been associated with beta human papillomavirus (β-HPV) infection-is increased by more than 100-fold in immunosuppressed patients. Previous studies have not established a causative role for HPVs in driving the development of skin cancer.

Efficacy of Home-Based Telerehabilitation vs In-Clinic Therapy for Adults After Stroke: A Randomized Clinical Trial.

Importance: Many patients receive suboptimal rehabilitation therapy doses after stroke owing to limited access to therapists and difficulty with transportation, and their knowledge about stroke is often limited. Telehealth can potentially address these issues.

Objectives: To determine whether treatment targeting arm movement delivered via a home-based telerehabilitation (TR) system has comparable efficacy with dose-matched, intensity-matched therapy delivered in a traditional in-clinic (IC) setting, and to examine whether this system has comparable efficacy for providing stroke education.

Skin cancer precursor immunotherapy for squamous cell carcinoma prevention.

Background: Topical calcipotriol plus 5-fluorouracil (5-FU) combination is an effective immunotherapy against actinic keratosis (AK), which is a precursor to squamous cell carcinoma (SCC). However, the long-term effectiveness of calcipotriol plus 5-FU treatment for SCC prevention is unknown.

Methods: We performed a blinded prospective cohort study on participants of a randomized double-blind clinical trial in which a 4-day course of topical calcipotriol plus 5-FU combination was compared to Vaseline plus 5-FU (control) for AK treatment.

Topical Combination of Fluorouracil and Calcipotriene as a Palliative Therapy for Refractory Extramammary Paget Disease.

Importance: Extramammary Paget disease (EMPD), a rare intraepithelial adenocarcinoma, poses a therapeutic challenge with high postoperative recurrence rates and a limited number of effective local treatment options.

Objective: To describe the use and efficacy of a topical combination of fluorouracil and calcipotriene as a palliative therapy for refractory EMPD.

Design, Setting, And Participants: This retrospective case series of 3 women with recurrent, refractory EMPD was conducted at Beth Israel Deaconess Medical Center, Boston, Massachusetts and Washington University School of Medicine, St Louis, Missouri.

IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation.

Chronic inflammation's tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. Studying the transition from acute, tumor-suppressive to chronic, tumor-promoting allergic contact dermatitis (ACD) revealed how tumor-promoting chronic inflammation develops. Epidermis-derived interleukin (IL)-33 up-regulation and its induction of regulatory T cell (Treg) accumulation in the skin preceded the transition from acute to chronic ACD and triggered the tumor-promoting immune environment in chronic ACD.

Chronic Inflammation Promotes Skin Carcinogenesis in Cancer-Prone Discoid Lupus Erythematosus.

High-risk skin cancer is a rare, but severe, complication associated with discoid lupus erythematosus (DLE). Chronic scar, inflammation, UVR, and immunosuppressive medications are proposed explanations for this heightened skin cancer risk; however, the exact mechanism driving skin carcinogenesis in DLE is unknown. The distinct co-localization of multiple independent skin cancers with areas of active inflammation in two DLE patients followed over 8 years strongly suggested that lupus inflammation promotes skin carcinogenesis in DLE.

Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis.

Advances in the field of cancer immunology, including studies on tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs), have led to new immunotherapeutics with proven efficacy against late-stage cancers. However, the antitumor potential of the immune system in targeting early-stage cancers remains uncertain. Here, we demonstrated that both genetic and chemical induction of thymic stromal lymphopoietin (TSLP) at a distant site leads to robust antitumor immunity against spontaneous breast carcinogenesis in mice.

Prevalence of prostate cancer in patients with chronic spinal cord injury.

Objective: To determine the prevalence of prostate cancer in patients with chronic spinal cord injury (SCI), with regard to the duration, level, and severity of injury.

Design: Retrospective chart review study.

Setting: Inpatient and outpatient Veterans Affairs spinal cord unit.

Electrodiagnostic findings and surgical outcome in isolated first branch lateral plantar neuropathy: a case series with literature review.

Two patients with recalcitrant unilateral heel pain and plantar fasciitis were referred for electrodiagnostic evaluation. They both reported constant, sharp, unilateral medial heel pain, with nocturnal symptoms, as well as exacerbation by weight-bearing activities. Examination of both patients demonstrated focal medial heel tenderness and a Tinel sign over the tarsal tunnel on the affected side.