Due to the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. The development of subtype-selective pharmaceutical small molecules to activate (agonists) signals regulated by D2-like receptors has been especially difficult.
Triple negative (progesterone receptor (PR)-, estrogen receptor (ER)-, human epidermal growth receptor 2 (HER2)-) breast cancer (TNBC) is an aggressive subtype that affects 15-20% of the 1.7 million cases of breast cancer occurring annually. Currently, standard treatments of TNBC include cytotoxic chemotherapies, surgery, and radiation. However, TNBC readily becomes resistant to chemotherapy, and those with TNBC are more likely to have a recurrence or die within five years compared to those with other breast cancer types.
T cells with T cell receptors (TCRs) for cancer-specific antigens are used for adoptive cell therapy (ACT), wherein a patient’s T cells are redirected against their own cancer. However, these isolated T cells may require further ex vivo manipulation to enhance their anti-tumor activity. The ex vivo manipulation of these T cells, or the selection of less functionally inert T cells, and genetic insertion of tumor specific TCRs may circumvent these limitations.
Some existing therapies for treatment of pain are administered systematically and have significant side effects, such as addiction and drowsiness. Alternative therapy that does not impair normal touch function could be used to treat pain caused by mechanical injury or chronic inflammation. Administration of margaric acid was shown to ameliorate pain in mouse models of pain. In vitro data shows that margaric acid counteracts PIEZO2 (Piezo-type mechanosensitive ion channel component 2) potentiation evoked by bradykinin (i.e.
Adoptive cell transfer (ACT) uses tumor infiltrating lymphocytes (TILs) that recognize unique antigens expressed by cancer cells (“neoantigens”). Neoantigen specific TIL administration in patients has resulted in long term regression of certain metastatic cancers. However, one of the challenges of ACT and engineered T cell receptor (TCR) therapies more broadly, is the identification and isolation of these mutation specific TILs and TCRs. Only a fraction of TILs in a given patient is known to be tumor reactive, while the majority are not useful for cell therapy.
Adoptive cell transfer (ACT) uses tumor infiltrating lymphocytes (TILs) that recognize antigens expressed by cancer cells (neoantigens). Neoantigen specific TIL administration in patients has resulted in long-term regression of certain metastatic cancers. However, current procedures for TIL therapy are highly invasive, labor-intensive, and time consuming. The success of these procedures is limited and differs between patients and histologies.
CD20 is a protein expressed by wide ranges of lymphoid malignancies originating from B cells but not by indispensable normal tissues, making it an attractive target for therapies such as T-cell receptor (TCR) therapy. Current anti-CD20 therapeutics face a number of limitations. The most important limitation to current anti-CD20 therapies include cancer cells becoming resistant to the therapy.
Recombinant Immunotoxins (RITs) are chimeric molecules composed of an antigen binding domain and toxin. The antigen binding domain component targets the cancer cell and delivers the toxin component to the cell. However, the efficacy of RITs is limited by their short half-life once they are in the patient. To address this problem, investigators at the National Cancer Institute (NCI) increased the half-life of RITs using polyethylene glycol (PEG).
Mutations in the cone rod homeobox (CRX) transcription factor lead to distinct retinopathy phenotypes, including early-onset vision impairment in dominant Leber congenital amaurosis (LCA). Adeno-Associated virus (AAV) vector-mediated delivery of a CRX cDNA under the control of a CRX promoter region partially restored photoreceptor phenotype and expression of phototransduction genes in an in vitro model of CRX-LCA.
Pancreatic ductal adenocarcinoma (PDA) accounts for more than 90% of pancreatic cancer cases, and it is one of the most aggressive malignancies with a 5-year survival rate of 6%. The high mortality rate caused by PDA is primarily from the lack of early diagnosis – it is often asymptomatic in early stages – and a poor response to conventional chemotherapy and radiotherapy. One of the major immune cell types present in the PDA microenvironment is a subset of macrophages commonly termed tumor-associated macrophages (TAM).