Jing Lü

Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

The CCAAT binding factor CBF is a heteromeric transcription factor, which binds to functional CCAAT motifs in many eukaryotic promoters. cDNAs for the A and B subunits of CBF (CBF-A and CBF-B) and for their yeast homologues HAP3 and HAP2 have been previously isolated, but the purified recombinant CBF-A and CBF-B together are unable to bind to CCAAT motifs in DNA. Here we report the isolation of a cDNA coding for rat CBF-C, demonstrate that recombinant CBF-C is required together with CBF-A and CBF-B to form a CBF-DNA complex, and show that CBF-C is present in this protein-DNA complex together with the other two subunits. We further show that CBF-C allows formation of a complex between the purified recombinant yeast HAP2 and HAP3 polypeptides and a CCAAT-containing DNA and is present in this complex, implying the existence of a CBF-C homologue in yeast. We show that CBF-A and CBF-C interact with each other to form a CBF-A-CBF-C complex and that CBF-B does not interact with CBF-A or CBF-C individually but that it associates with the CBF-A-CBF-C complex. Our results indicate that CBF is a unique evolutionarily conserved DNA binding protein.

<p>Despite exciting progress in the understanding of breast cancerdevelopment and progression, and in the development of noveltherapeutic strategies, breast cancer remains the second leadingcause of cancer-related death in women, with a yearly toll of morethan 40,000 deaths in the United States alone. Breast cancer–relateddeaths are mainly due to the “incurable” nature of metastaticbreast cancer (MBC) at the current time. It is estimated that?6% of patients have metastatic disease at the time of diagnosisand 20% to 50% patients first diagnosed with primary breast cancerwill eventually develop metastatic disease. Even with the remarkableadvances in research and clinical management, thecurrent treatment strategies for breast cancer metastasis stilllargely rely on the use of systemic cytotoxic agents, which frequentlydeteriorate the patient's life quality due to severe sideeffects and, in many cases, have limited long-term success. Theprognosis for MBC patients is poor, with an estimated 5-year survivalof only 26%. Therefore, MBC remains the most challengingtask facing both cancer researcher and oncologist. To tackle thischallenge, scientists and physicians of the Breast Cancer ResearchProgram at the M.D. Anderson Cancer Center held a symposium to(a) provide a better understanding of breast cancer metastasis atthe molecular and cellular level; (b) introduce cutting-edge technologiesin metastatic breast cancer detection, including clinicopathologicdetection, circulating tumor cells (CTC) detection, andadvanced imaging; and (c) solicit innovative ideas in basic, translationalresearch and clinical patient management. The symposiumled to a positive consensus notion that we will be able to prevent,and to a lesser degree, treat metastasis and ultimately save mostpatients from metastatic deaths in the foreseeable future.</p>