Alpha Particle-Emitting Radiopharmaceuticals as Cancer Therapy: Biological Basis, Current Status, and Future Outlook for Therapeutics Discovery.

Critical advances in radionuclide therapy have led to encouraging new options for cancer treatment through the pairing of clinically useful radiation-emitting radionuclides and innovative pharmaceutical discovery. Of the various subatomic particles used in therapeutic radiopharmaceuticals, alpha (α) particles show great promise owing to their relatively large size, delivered energy, finite pathlength, and resulting ionization density. This review discusses the therapeutic benefits of α-emitting radiopharmaceuticals and their pairing with appropriate diagnostics, resulting in innovative "theranostic" platforms. Herein, the current landscape of α particle-emitting radionuclides is described with an emphasis on their use in theranostic development for cancer treatment. Commonly studied radionuclides are introduced and recent efforts towards their production for research and clinical use are described. The growing popularity of these radionuclides is explained through summarizing the biological effects of α radiation on cancer cells, which include DNA damage, activation of discrete cell death programs, and downstream immune responses. Examples of efficient α-theranostic design are described with an emphasis on strategies that lead to cellular internalization and the targeting of proteins involved in therapeutic resistance. Historical barriers to the clinical deployment of α-theranostic radiopharmaceuticals are also discussed. Recent progress towards addressing these challenges is presented along with examples of incorporating α-particle therapy in pharmaceutical platforms that can be easily converted into diagnostic counterparts.

Targeted Inhibition of DNA-PKcs, ATM, ATR, PARP, and Rad51 Modulate Response to X Rays and Protons.

Small molecule inhibitors are currently in preclinical and clinical development for the treatment of selected cancers, particularly those with existing genetic alterations in DNA repair and DNA damage response (DDR) pathways. Keen interest has also been expressed in combining such agents with other targeted antitumor strategies such as radiotherapy. Radiotherapy exerts its cytotoxic effects primarily through DNA damage-induced cell death; therefore, inhibiting DNA repair and the DDR should lead to additive and/or synergistic radiosensitizing effects. In this study we screened the response to X-ray or proton radiation in cell lines treated with DDR inhibitors (DDRis) targeting ATM, ATR, DNA-PKcs, Rad51, and PARP, with survival metrics established using clonogenic assays. We observed that DDRis generate significant radiosensitization in cancer and primary cells derived from normal tissue. Existing genetic defects in cancer cells appear to be an important consideration when determining the optimal inhibitor to use for synergistic combination with radiation. We also show that while greater radiosensitization can be achieved with protons (9.9 keV/µm) combined with DDRis, the relative biological effectiveness is unchanged or in some cases reduced. Our results indicate that while targeting the DDR can significantly radiosensitize cancer cells to such combinations, normal cells may also be equally or more severely affected, depending on the DDRi used. These data highlight the importance of identifying genetic defects as predictive biomarkers of response for combination treatment.

An empirical model of proton RBE based on the linear correlation between x-ray and proton radiosensitivity.

BACKGROUND: Proton relative biological effectiveness (RBE) is known to depend on physical factors of the proton beam, such as its linear energy transfer (LET), as well as on cell-line specific biological factors, such as their ability to repair DNA damage. However, in a clinical setting, proton RBE is still considered to have a fixed value of 1.1 despite the existence of several empirical models that can predict proton RBE based on how a cell's survival curve (linear-quadratic model [LQM]) parameters α and ß vary with the LET of the proton beam. Part of the hesitation to incorporate variable RBE models in the clinic is due to the great noise in the biological datasets on which these models are trained, often making it unclear which model, if any, provides sufficiently accurate RBE predictions to warrant a departure from RBE = 1.1. PURPOSE: Here, we introduce a novel model of proton RBE based on how a cell's intrinsic radiosensitivity varies with LET, rather than its LQM parameters. METHODS AND MATERIALS: We performed clonogenic cell survival assays for eight cell lines exposed to 6 MV x-rays and 1.2, 2.6, or 9.9 keV/µm protons, and combined our measurements with published survival data (n = 397 total cell line/LET combinations). We characterized how radiosensitivity metrics of the form DSF% , (the dose required to achieve survival fraction [SF], e.g., D10% ) varied with proton LET, and calculated the Bayesian information criteria associated with different LET-dependent functions to determine which functions best described the underlying trends. This allowed us to construct a six-parameter model that predicts cells' proton survival curves based on the LET dependence of their radiosensitivity, rather than the LET dependence of the LQM parameters themselves. We compared the accuracy of our model to previously established empirical proton RBE models, and implemented our model within a clinical treatment plan evaluation workflow to demonstrate its feasibility in a clinical setting. RESULTS: Our analyses of the trends in the data show that DSF% is linearly correlated between x-rays and protons, regardless of the choice of the survival level (e.g., D10% , D37% , or D50% are similarly correlated), and that the slope and intercept of these correlations vary with proton LET. The model we constructed based on these trends predicts proton RBE within 15%-30% at the 68.3% confidence level and offers a more accurate general description of the experimental data than previously published empirical models. In the context of a clinical treatment plan, our model generally predicted higher RBE-weighted doses than the other empirical models, with RBE-weighted doses in the distal portion of the field being up to 50.7% higher than the planned RBE-weighted doses (RBE = 1.1) to the tumor. CONCLUSIONS: We established a new empirical proton RBE model that is more accurate than previous empirical models, and that predicts much higher RBE values in the distal edge of clinical proton beams.

Effect of boron compounds on the biological effectiveness of proton therapy.

PURPOSE: We assessed whether adding sodium borocaptate (BSH) or 4-borono-l-phenylalanine (BPA) to cells irradiated with proton beams influenced the biological effectiveness of those beams against prostate cancer cells to investigate if the alpha particles generated through proton-boron nuclear reactions would be sufficient to enhance the biological effectiveness of the proton beams. METHODS: We measured clonogenic survival in DU145 cells treated with 80.4-ppm BSH or 86.9-ppm BPA, or their respective vehicles, after irradiation with 6-MV X-rays, 1.2-keV/µm (low linear energy transfer [LET]) protons, or 9.9-keV/µm (high-LET) protons. We also measured γH2AX and 53BP1 foci in treated cells at 1 and 24 h after irradiation with the same conditions. RESULTS: We found that BSH radiosensitized DU145 cells across all radiation types. However, no difference was found in relative radiosensitization, characterized by the sensitization enhancement ratio or the relative biological effectiveness, for vehicle- versus BSH-treated cells. No differences were found in numbers of γH2AX or 53BP1 foci or γH2AX/53BP1 colocalized foci for vehicle- versus BSH-treated cells across radiation types. BPA did not radiosensitize DU145 cells nor induced any significant differences when comparing vehicle- versus BPA-treated cells for clonogenic cell survival or γH2AX and 53BP1 foci or γH2AX/53BP1 colocalized foci. CONCLUSIONS: Treatment with 11 B, at concentrations of 80.4 ppm from BSH or 86.9 ppm from BPA, had no effect on the biological effectiveness of proton beams in DU145 prostate cancer cells. Our results agree with published theoretical calculations indicating that the contribution of alpha particles from such reactions to the total absorbed dose and biological effectiveness is negligible. We also found that BSH radiosensitized DU145 cells to X-rays, low-LET protons, and high-LET protons but that the radiosensitization was not related to DNA damage.

Two new species of Platensina Enderlein (Diptera, Tephritidae, Tephritinae, Dithrycini) from India.

Two new species of Platensina Enderlein, P.rabbanii David & Hancock, sp. nov., and P.flavistigma David & Hancock, sp. nov., are described from Meghalaya and southern India, respectively. Platensinarabbanii can be differentiated from P.alboapicalis Hering by the presence of a single hyaline indentation in cell r1 and the apical hyaline band in cell r2+3 restricted to the apex; P.flavistigma differs from P.quadrula Hardy by the presence of a yellow/fulvous pterostigma and shape of the epandrium. DNA barcode sequences of P.acrostacta (Wiedemann), P.flavistigma and P.platyptera Hendel were obtained and reported. Postabdominal descriptions and illustrations of P.acrostacta, P.platyptera and P.zodiacalis (Bezzi) are also provided along with keys to all 23 species and the 7 known from India.

A new genus of fruit fly in subfamily Dacinae (Diptera: Tephritidae) from India.

A new genus and species of fruit fly, Dacimita curvifasciatus David & Hancock, gen. et sp. n. is described from Meghalaya, India. It morphologically resembles Ichneumonopsis Hardy and Monacrostichus Bezzi, the former of uncertain tribal placement and the latter included in tribe Dacini. Phylogenetic analysis based on morphological and molecular characters revealed Dacimita curvifasciatus to be best placed in tribe Gastrozonini in subfamily Dacinae.

A new species of the genus Asobara Foerster (Hymenoptera: Braconidae) parasitic on Zeugodacus cucurbitae (Coquillett) (Diptera: Tephritidae) infesting tomato in India.

Asobara jenningsi Gupta sp. nov., a new parasitoid of the braconid genus, is described and illustrated from Karnataka, India. The new species is compared with all the possible closely allied species from the Oriental region.

Taxonomic notes on the genus Elaphromyia Bigot (Diptera: Tephritidae: Tephritinae: Pliomelaenini) in India, with description of a new species.

A new species of Elaphromyia, E. juncta David, Hancock Sachin, sp. n. is described from India. It can be differentiated from the morphologically similar E. siva Frey and E. pterocallaeformis (Bezzi) by the wing pattern, epandrial characters, morphology of spicules on the eversible membrane and spermathecal shape. Elaphromyia siva Frey and E. yunnanensis Wang are recorded for the first time from India. Records of E. pterocallaeformis (Bezzi) from southern India are regarded as misidentifications. A key to the 7 known non-African species is included.

A new species, new postabdominal descriptions and a new synonymy in Euphranta Loew (Diptera: Tephritidae: Trypetinae: Adramini).

A new species of Euphranta, E. flavothoracica David, Hancock Sachin, sp. n. is described from India and placed in the zeylanica group of species. Postabdominal structures of E. cassiae (Munro), E. crux (Fabricius) and E. klugii (Wiedemann) are described. A revised key to the 16 species of Euphranta known from India is provided. A new generic and specific synonymy is established: Euphranta Loew, 1862 = Ichneumonomacula Chen, 2020, syn. n. and Dacus figuratus Walker, 1856 (=Euphranta figurata (Walker, 1856))= Ichneumonomacula wangyongi Chen, 2020, syn. n.

A new species of Euphranta Loew (Diptera: Tephritidae: Trypetinae: Adramini) from India.

A new species of Euphranta Loew, E. siruvani David, Hancock Sankararaman, sp. n. is described from India. Postabdominal structures of E. hyalipennis David Freidberg and E. haldwanica Hancock Goodger are illustrated and described. A revised key to Euphranta from India is also provided.

A new species of Acrotaeniostola Hendel and new records of Gastrozonini and Ceratitidini (Diptera: Tephritidae) from India.

A new species of Acrotaeniostola Hendel, A. connexa sp. n. of tribe Gastrozonini, is described from India. Acroceratitis incompleta Hardy of tribe Gastrozonini and Ceratitella sobrina (Zia) of tribe Ceratitidini have been recorded for the first time from India. The genus Ceratitella Malloch and tribe Ceratitidini are recorded for the first time from India.

TWO NEW SPECIES AND A NEW RECORD OF DACUS FABRICIUS (DIPTERA: TEPHRITIDAE) FROM INDIA.

Two new species of the genus Dacus Fabricius, namely D. (Mellesis) jacobi David Sachin and D. (Mellesis) viraktamathi David Hancock of tribe Dacini are described from India. Dacus (Mellesis) maculipterus White is recorded for the first time from India. An updated key to species of genus Dacus from India, Bhutan and Sri Lanka is also provided.

A new species of Hemilea Loew and two new records of Trypetini (Diptera: Tephritidae: Trypetinae) from India.

A new species of Hemilea Loew, H. totu David, Hancock Sachin, sp. n., is described from India. Paratrypeta appendiculata (Hendel) and Vidalia thailandica Hancock Drew are recorded for the first time from India and a key to species of Hemilea from India and Myanmar is provided.

Erratum: K. J. DAVID amp; D. L. HANCOCK (2019) TAXONOMIC NOTES ON GENUS COELOTRYPES BEZZI (DIPTERA: TEPHRITIDAE: TRYPETINAE) WITH DESCRIPTION OF TWO NEW SPECIES ZOOTAXA, 4563: 584-594.

N/A.

Taxonomic notes on genus Coelotrypes Bezzi (Diptera: Tephritidae: Trypetinae) with description of two new species.

Two new species of Coelotrypes Bezzi, C. meremmiae sp. n. and C. paralatilimbatus sp. n. are described from India. Postabdominal structures and the third instar larva of C. luteifasciatus (Senior-White) are also illustrated and described. A key to Oriental species of Coelotrypes is provided.

New species, redescriptions and phylogenetic revision of tribe Dacini (Diptera: Tephritidae: Dacinae) from India based on morphological characters.

The tribe Dacini comprising four genera, namely Bactrocera Macquart, Dacus Fabricius, Monacrostichus Bezzi and Zeugodacus Hendel, is a derived lineage in Tephritidae. It is one of the most economically important tribes in Tephritidae harbouring several species of quarantine concern across the world. We describe two new species of Bactrocera Macquart, B. (Parazeugodacus) conica David Ramani, sp. n. B. (B.) prabhui David, sp. n. from India. Postabdominal structures of males and/or females of 23 species of Bactrocera, 16 species of Zeugodacus and 8 species of Dacus from India are illustrated and described for the first time, which revealed similarities between Dacus and Zeugodacus with respect to epandrial shape and praeputium patterning. Bactrocera is unique in possessing oval shaped epandrium and an unpatterned praeputium. An analysis of phylogenetic relationships between three genera of the tribe Dacini from India based on morphological characters has been attempted for the first time. Cladistic analysis employing 51 characters of 62 species in Dacini, with seven species as outgroups revealed the monophyly of Dacini, Bactrocera and Dacus with supporting nonhomplasious synapomorphies. Ichneumonopsis Hardy, often included in the Gastrozonini, does not possess any synapomorphies of Dacini, eventhough it appeared at the base of the Dacini clade. Zeugodacus was retrieved as a monophyletic sister-group to Dacus based solely on a single homoplasious host plant character, with weak statistcal support.

Regulatory pathways to enable the licencing of alternatives to antibiotics.

Effective alternatives to antibiotics (ATA) such as vaccines, antibodies, phage therapies, prebiotics, probiotics and herbal medicines can be used in place of traditional antibiotics in a way that does not compromise animal health as means of tackling the growing threat to both animal and human health from antimicrobial resistance (AMR). This paper reflects the key points on the approaches that were discussed during the 2nd International Symposium on ATA between regulatory agencies, veterinary product companies representing largely the pharmaceutical and feed-additive sectors, academia and other stakeholders on regulatory pathways to enable the licensing of alternatives to antibiotics for food producing animals. The need to demonstrate compliance with generally accepted standards for quality, safety and efficacy is considered a pre-requisite for all veterinary medicinal products receiving an authorisation including ATA, irrespective of the region in which they are approved. ATA are often based on novel technologies, with complex mechanisms of action; therefore, early and close communication with regulators is encouraged. In addition, strategic use by ATA applicants of all regulatory tools available to support innovation is highly recommended. The veterinary product manufacturers consider that the regulation of veterinary medicines should evolve to accommodate innovative ATA technologies and incentives from regulatory agencies provided to stimulate further ATA development.

New species, new records and updated subgeneric key of Bactrocera Macquart (Diptera: Tephritidae: Dacinae: Dacini) from India.

Two new species of genus Bactrocera Macquart, namely B. (Sinodacus) brevipunctata David and Hancock, sp. nov. and B. (Bactrocera) furcata David and Hancock, sp. nov., are described from India. B. (B.) aethriobasis Hardy, B. (B.) rubigina Wang & Zhao, B. (B.) syzygii Tsuruta & White and B. (B.) tuberculata (Bezzi) are recorded for the first time from India. Updated keys to twelve subgenera of Bactrocera and Indian species of Bactrocera (Bactrocera) are also provided.

A new species of Gastrozona Bezzi (Diptera: Tephritidae: Dacinae: Gastrozonini) with an updated key to species from India.

Gastrozona nigrifemur sp. nov., is described from India. Postabdominal structures of G. fasciventris (both male and female), G. soror (female) and G. montana (male) are described and illustrated. An updated key to Indian species of Gastrozona is provided.

Two new species and a new record of Bactrocera Macquart (Diptera: Tephritidae: Dacinae: Dacini) from India.

Two new species of Bactrocera Macquart, namely Bactrocera (Calodacus) harrietensis Ramani & David, sp. nov. and Bactrocera (Calodacus) chettalli David & Ranganath, sp. nov., are described from the Andaman and Nicobar Islands and Karnataka, India, respectively. Bactrocera (Zeugodacus) semongokensis Drew & Romig is recorded for the first time from India.