Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

Improvement in plan quality after Implementation of clinical goals in a large network of cancer centers.

Clinical Goals (CG) is a tool available in the Varian Eclipse planning system to objectively and visually evaluate the quality of treatment plans based upon user-defined dose-volume parameters. We defined a set of CG for Stereotactic Radiosurgery (SRS) and Intensity-Modulated Radiotherapy (IMRT) based on published data and guidelines and implemented this in a network of cancer centers in India (American Institute of Oncology). A dosimetric study was performed to compare brain SRS and breast IMRT plan quality before and after CG implementation.The CG defined for SRS plans were target V100% ≥ 98%, dose gradient measure (GM) ≤ 0.5 cm, conformity index (CI) 1.0 to 1.2. For breast IMRT plans, CG defined target V100% ≥ 97%, V95% ≥ 95%, V107% ≤ 2%, V105% ≤ 10%, and Dmax ≤ 2.4 Gy. Dose limits to organs-at-risk (OAR) were summarize in supplemental materials. Twenty brain SRS and 10 breast IMRT treatment plans that were previously delivered on patients were selected and re-planned using CG. The pre and postoptimized plan parameters were compared using student t-tests.For brain SRS plans, the V100, GM, and CI for the pre- and post-Clinical-Goals plans were 93.22% ± 7.2% vs 97.96% ± 0.29% (p = 0.009), 0.63 ± 0.16 vs 0.42 ± 0.05 (p < 0.001) and 1.07 ± 0.18 vs 1.06 ± 0.06 (p = 0.79), respectively. There were no differences in max dose to OARs. In breast IMRT plans, the target V107% for pre and postimplemented plans were 16.50% ± 10.98% vs 0.32% ± 0.32%, respectively (p = 0.001). The average target V105% were 44.00% ± 15.72% and 8.69% ± 4.53%, respectively (p < 0.001). No differences were found in the average target V100% (p = 0.128) and V95% (p = 0.205). The average target Dmax were 112.28% ± 1.59% and 109.14% ± 0.73%, respectively (p < 0.001). There were only minor differences in doses to OARs.The implementation of CG in Varian Eclipse significantly improved SRS and IMRT plan quality with enhanced coverage, dose GM, and CI without increased dose to OARs.

Involvement of glutamine synthetase 2 (GS2) amplification and overexpression in Amaranthus palmeri resistance to glufosinate.

MAIN CONCLUSION: Amplification and overexpression of the target site glutamine synthetase, specifically the plastid-located isoform, confers resistance to glufosinate in Amaranthus palmeri. This mechanism is novel among glufosinate-resistant weeds. Amaranthus palmeri has recently evolved resistance to glufosinate herbicide. Several A. palmeri populations from Missouri and Mississippi, U.S.A. had survivors when sprayed with glufosinate-ammonium (GFA, 657 g ha-1). One population, MO#2 (fourfold resistant) and its progeny (sixfold resistant), were used to study the resistance mechanism, focusing on the herbicide target glutamine synthetase (GS). We identified four GS genes in A. palmeri; three were transcribed: one coding for the plastidic protein (GS2) and two coding for cytoplasmic isoforms (GS1.1 and GS1.2). These isoforms did not contain mutations associated with resistance. The 17 glufosinate survivors studied showed up to 21-fold increase in GS2 copies. GS2 was expressed up to 190-fold among glufosinate survivors. GS1.1 was overexpressed > twofold in only 3 of 17, and GS1.2 in 2 of 17 survivors. GS inhibition by GFA causes ammonia accumulation in susceptible plants. Ammonia level was analyzed in 12 F1 plants. GS2 expression was negatively correlated with ammonia level (r = - 0.712); therefore, plants with higher GS2 expression are less sensitive to GFA. The operating efficiency of photosystem II (ϕPSII) of Nicotiana benthamiana overexpressing GS2 was four times less inhibited by GFA compared to control plants. Therefore, increased copy and overexpression of GS2 confer resistance to GFA in A. palmeri (or other plants). We present novel understanding of the role of GS2 in resistance evolution to glufosinate.

Cancer stem cell populations in lymphoma in dogs and impact of cytotoxic chemotherapy.

Cancer relapse following chemotherapy has been attributed in part to the presence of cancer stem cells (CSC), which drive tumour growth and metastasis and are highly resistant to the effects of cytotoxic chemotherapy. As a result, treatment with cytotoxic chemotherapy selects for drug-resistant CSC populations that eventually drive tumour recurrence. Little is known currently regarding the role of CSC in dogs with lymphoma, nor the impact of chemotherapy on CSC populations. Therefore, we prospectively quantitated CSC populations in dogs with B-cell (BCL) and T-cell lymphoma (TCL), using tumour aspirates and flow cytometric analysis with a panel of CSC markers. In addition, in vitro studies were carried out to determine the impact of chemotherapy resistance on the stem cell phenotype and stem cell properties of lymphoma cells. We found that the percentages of tumour cells expressing CSC markers were significantly increased in dogs with BCL, compared with B cells from normal lymph nodes. Similar findings were observed in dogs with TCL. In vitro studies revealed that lymphoma cells selected for resistance to CHOP chemotherapy had significantly upregulated expression of CSC markers, formed spheroids in culture more readily, and expressed significantly greater aldehyde dehydrogenase activity compared with chemotherapy-sensitive tumour cells. Similar results were observed in tumour samples dogs with relapsed BCL. These findings suggest that cytotoxic chemotherapy can lead to a relative enrichment of tumour cells with CSC properties, which may be associated with lymphoma recurrence.

Cymetra.

Soft tissue replacement using a filler as a temporary scaffold to encourage revascularization and tissue in growth is an exciting concept. Sheets of acellular human dermal matrix, called Alloderm (Lifecell Corp, Branchburg, NJ), have been shown to do just that. When implanted into a patient, tissue growth and revascularization have both been observed. The company manufactures a micronized or injectable form called Cymetra. This article reviews the manufacturing, tissue interaction, clinical applications, and anticipated clinical results.

Gamma knife subthalamotomy for Parkinson disease: the subthalamic nucleus as a new radiosurgical target. Case report.

The authors present the neuroimaging, treatment planning, and radiosurgical technique for the first reported case of unilateral radiosurgical subthalamotomy, which was performed to control motor symptoms associated with advanced Parkinson disease (PD) in a patient who had undergone previous contralateral radiofrequency (RF) pallidotomy. A 73-year-old woman with end-stage PD had undergone RF pallidotomy of the right globus pallidus with resolution of symptoms. Two years following this procedure, due to the natural progression of her disease, she suffered recurrent motor fluctuations, dyskinesia, and worsening bradykinesia of the right side. Her Parkinson's Disease Disability Rating (PDDR) score was 28. Computerized tomography and magnetic resonance (MR) imaging were used to localize the left subthalamic nucleus (STN). The patient underwent gamma knife radiosurgery-a single shot of 120 Gy was administered using the 4-mm collimator helmet. The patient was evaluated up to 42 months after the procedure. The dyskinesia became minimal. Right-sided motor control improved as did her balance. At 3 months after treatment MR imaging demonstrated the radiosurgical lesion in the left STN. At 3.5 years postradiosurgery, she experienced minimal focal (oral) dyskinesia, no bradykinesia or rigidity, and her PDDR score was 11. Radiosurgery of the STN in this case was safe and effective. The STN is a readily localized anatomical target with neuroimaging. Radiosurgery avoids the risks of open procedures.