Biological activity of a stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor, 60c, in metastatic, triple-negative breast cancer.

BACKGROUND: Improving survival for patients diagnosed with metastatic disease and overcoming chemoresistance remain significant clinical challenges in treating breast cancer. Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by a lack of therapeutically targetable receptors (ER/PR/HER2). TNBC therapy includes a combination of cytotoxic chemotherapies, including microtubule-targeting agents (MTAs) like paclitaxel (taxane class) or eribulin (vinca class); however, there are currently no FDA-approved MTAs that bind to the colchicine-binding site. Approximately 70 % of patients who initially respond to paclitaxel will develop taxane resistance (TxR). We previously reported that an orally bioavailable colchicine-binding site inhibitor (CBSI), VERU-111, inhibits TNBC tumor growth and treats pre-established metastatic disease. To further improve the potency and metabolic stability of VERU-111, we created next-generation derivatives of its scaffold, including 60c. RESULTS: 60c shows improved in vitro potency compared to VERU-111 for taxane-sensitive and TxR TNBC models, and suppress TxR primary tumor growth without gross toxicity. 60c also suppressed the expansion of axillary lymph node metastases existing prior to treatment. Comparative analysis of excised organs for metastasis between 60c and VERU-111 suggested that 60c has unique anti-metastatic tropism. 60c completely suppressed metastases to the spleen and was more potent to reduce metastatic burden in the leg bones and kidney. In contrast, VERU-111 preferentially inhibited liver metastases and lung metastasis repression was similar. Together, these results position 60c as an additional promising CBSI for TNBC therapy, particularly for patients with TxR disease.

Stevens-Johnson Syndrome in a Patient on Concomitant Treatment with Levetiracetam and Trimethoprim/Sulfamethoxazole.

BACKGROUND Trimethoprim/sulfamethoxazole and levetiracetam are commonly prescribed medications in the treatment of infections and seizures, respectively. Despite their known efficacy, each has a reputation for triggering severe and sometimes life-threatening cutaneous adverse drug reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Although the mechanism of such cutaneous adverse drug reactions cannot be fully explained, it is thought to be a type IV T cell and NK cells-mediated hypersensitivity reaction that leads to keratinocyte apoptosis and epidermal necrosis. It is also thought that cutaneous adverse drug reactions are also linked to a patient's genetic predispositions, especially the human leukocyte antigens profiles and the N-acetyl transferase 2 phenotypic variation. CASE REPORT We describe a case of Stevens-Johnson syndrome in a severely ill 51-year-old man who was treated in an outside health care facility simultaneously with Trimethoprim/sulfamethoxazole and levetiracetam. The patient presented to our Emergency Department with Stevens-Johnson syndrome believed to possibly be related to the combination of these 2 agents. CONCLUSIONS The concomitant use of Trimethoprim/sulfamethoxazole and levetiracetam might have been responsible for heightening the potential of these 2 medications to trigger an unfortunate adverse drug reaction, but no formal culprit was able to be identified and no in vivo study was performed, due to ethical considerations. Thus, through this case report we strive to increase awareness of the potential risk of simultaneously prescribing these 2 medications.

CAR T cell therapy in solid tumors: A review of current clinical trials.

Chimeric antigen receptor (CAR) T cell therapy has made tremendous strides in the arena of hematological malignancies with approved therapies in certain leukemias, lymphomas, and recently myeloma with overall highly favorable response rates. While numerous clinical studies are still ongoing for hematological malignancies, research is developing to translate the feasibility of CAR T therapy in solid organ malignancies. Unfortunately, the majority of diagnosed cancers are primarily solid tumors. Thus, a highly unmet clinical need for further research and development exists in this field. This review article highlights currently active clinical trials and a few pertinent preclinical studies involving CAR T cell therapy in solid tumors while briefly discussing study outcomes and potential key targets that may allow for the feasibility of this therapy option. Finally, we mention critical challenges existing in the solid tumor environment and discuss developing strategies that may potentially overcome the existing barriers to CAR T cell progress in solid tumors.