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KRAS is genomically altered in about one third of all human tumors. Due to its central role in oncogenesis, many attempts have been made in the last four decades to drug mutant KRAS, either directly or indirectly. Despite recent advances in targeting KRAS using small molecule inhibitors, the majority of KRAS alterations do not yet have an existing targeted therapy, and where inhibitors are available, resistance rapidly emerges. Thus, novel approaches to drugging KRAS are needed. Eliminating mutant KRAS using a targeted protein degradation approach may lead to superior efficacy relative to inhibiting the protein. KRAS PROTAC® degraders that selectively target the G12D mutant form of KRAS were identified and profiled in KRAS-dependent cancer models. In vitro, PROTAC degraders targeting the G12D mutant degrade KRAS with picomolar potency, robustly suppress MAPK and PI3K/AKT signaling, induce apoptosis, and have antiproliferative activity that is superior to known inhibitors. These molecules are selective for mutant KRAS G12D, neither degrading wild-type KRAS nor the related isoforms HRAS and NRAS. In vivo, these degraders can eliminate >95% of mutant KRAS from relevant xenograft models, induce apoptosis, and lead to tumor regression. Consistent with the extended pharmacodynamics often observed with PROTAC degraders, a single dose of a G12D PROTAC results in prolonged KRAS degradation and significant pERK suppression up to one week after administration. Combined, these data show that degrading mutant KRAS G12D in tumors is highly efficacious and may have advantages over inhibition, making it an exciting potential new approach for the treatment of KRAS mutant cancers. Citation Format: Kathryn Smith, Andrea Lopez-Arroyo, Jason Berk, Peter Hegan, Peter Nower, Samantha Tice, Aurelie Moutran, Jennifer Pizzano, Amanda Dowtin, Mark Bookbinder, Elizabeth Bortolon, Greg Cadelina, Fazlul Karim, Katie Digianantonio, Miklos Bekes, Jesus Medina. KRAS-targeted PROTAC degraders are broadly efficacious against KRAS-dependent tumor models [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr PR09.

No abstract

Abstract. Bisphosphonates consist of a family of pyrophosphate analogues that are currently being used to treat metastatic bone diseases as well as systemic bone diseases such as osteoporosis. There is accumulating evidence suggesting that patients treated with these bisphosphonates can develop, particularly with invasive dental procedures, osteonecrosis of the jaw. This present study investigated the ability of osteoblastic cells obtained from the alveolar bone of patients on long term intravenous bisphosphonate therapy to respond to agents normally involved in bone regulation and repair. The effects of platelet-derived growth factor-BB (PDGF-BB), 1,25-dihydroxycholecalciferol [1,25(OH) 2 VitaminD 3 ] and parathyroid hormone (PTH) on basic parameters of cell viability, proliferation, and differentiation were studied. Osteoblastic cells from a diagnosed necrotic alveolar bone specimen obtained with consent from a multiple myeloma female patient, and a non-necrotic sample from a breast cancer female patient both on chronic bisphosphonate therapy (zolendronic acid) were successfully cultured. Cells from an alveolar bone specimen obtained from a female donor with no known medical conditions were also studied for comparative responses. The cells were exposed to 1,25(OH) 2 D 3 , PDGF, or PTH under various incubation conditions. The osteoblastic cell differentiation marker, alkaline phosphatase activity, was assayed using a biochemical analysis. Cell viability was assessed with an MTT assay which measures mitochondrial activity and cell proliferation with a tritiated thymidine assay. This study on osteoblastic cells grown from a necrotic alveolar bone from a multiple myeloma patient and a non-necrotic sample from a breast cancer patient, both on long term bisphosphonate treatment, suggests that viable cells from the bone are responsive to agents such as PTH, PDGF and 1,25(OH) 2 D 3 with changes in alkaline phosphatase activity, proliferation and viability suggestive of normal osteoblastic cell responses observed in cultures from a donor of the same gender and age, but not on bisphosphonate treatment. This work provides a rationale for clinical studies to further assess whether the osteonecrosis that sometimes develops in patients treated with bisphosphonates, can be controlled or prevented by close attention to the levels of bone/calcium regulatory agents and/or, in some cases, therapeutic intervention with PDGF to restore regenerative processes that may be compromised at the necrotic site.

surface of the left femoral head. The patient underwent elective surgical dislocation of left hip for removal of the intra-articular pellet. Setting: Inpatient rehabilitation. Results: After surgery, the patient had pain relief in the left hip, with no pain on movements. The patient was started on weight bearing as tolerated on the right lower extremity while keeping the left lower extremity nonweight bearing, which proved to be a major challenge for ambulation. However, within a week, the patient was able to fully weight bear on his right lower extremity while remaining nonweight bearing on the Left because of the elective dislocation. Discussion: Pellets lodged within bone are usually left in place if they do not compromise the structural integrity of the bone. However, if it is lodged on the articular surface or is intra-articular, it can result in articular cartilage damage and cause pain on movement. Conclusions: Pellets lodged in the bone close to the joint may give the false appearance of being buried in the bone on plain x-ray films. However, further imaging with computed tomography may be required to rule out intra-articular extension or loose fragments in the joint, to avoid pain and cartilage damage. Bilateral hip injury, although poses a rehabilitation challenge, can be rewarding with early ambulation while observing standard precautions.