Resistance against PSMA-targeting alpha-radiation therapy coincides with mutations in DNA-repair associated genes

Twins in spirit part IV – [177Lu] high affinity DOTATATE

“…A meta-analysis by Kim et al (11) demonstrated disease response rates ranging between 17.6 and 43.8 % with a pooled effect of 29 % (95 % confidence interval [CI] 24-34 %) according to RECIST. Therefore, attempts at achieving better outcomes are still in the focus of scientific interest (10,(13)(14)(15)24).…”

Targeted Alpha Therapy, an Emerging Class of Cancer Agents

“…For instance, the alpha particleemitter radium 223 is a calcium-mimetic isotope that is incorporated into sites of increased bone turnover and osteoblastic activity (Figure 1A). [1][2][3][4][5] The second approach conjugates alpha particleemitting radionuclides to monoclonal antibodies (mAbs) (Figure 1B), 1,2 peptides, or small molecules to target tumor-associated antigens (Figure 1C), 1,2 allowing for the possibility of targeting a wide range of tumor types. 1,6 The emission of short-range alpha particles causes complex double-stranded DNA breaks through high linear-energy transfer (LET), triggering cell death and, importantly, having no known resistance mechanism.…”

“…[1][2][3][4][5] The second approach conjugates alpha particleemitting radionuclides to monoclonal antibodies (mAbs) (Figure 1B), 1,2 peptides, or small molecules to target tumor-associated antigens (Figure 1C), 1,2 allowing for the possibility of targeting a wide range of tumor types. 1,6 The emission of short-range alpha particles causes complex double-stranded DNA breaks through high linear-energy transfer (LET), triggering cell death and, importantly, having no known resistance mechanism. 5,7,8 Delivering short-range, high-energy radia-tion in a targeted manner may allow for the treatment of localized or metastatic tumors 9 with minimal toxic effects to surrounding noncancerous tissue.…”

“…C, Small-molecule-mediated TαT. The example shown is actinium 225 conjugated to DOTA [(CH 2 CH 2 NCH 2 CO 2 H) 4 ]-based prostate-specific membrane antigen 617 (PSMA-617), 1 which targets and delivers actinium 225 to PSMA-expressing prostate cancer cells. Adapted from chapter 4 in Biomedical Engineering-Frontiers and Challenges under CC-BY-NC-SA 3.0 license.…”

“…Examples include the conjugation of thorium 227 to a full-length mesothelin antibody to target mesothelin-expressing cancer cells and the conjugation of actinium 225 to the small-molecule, prostate-specific membrane antigen 617 to target prostate cancer cells. 1,36 The use of these targeting moieties results in shorter serum half-lives and rapid targeted uptake into tumors. 14,35 However, the use of affibodies and nanobodies can result in increased risk of offtarget toxic effects, notably renal toxic effects due to increased renal retention.…”