UCK2-targeting compound for use in detecting and treating UCK2 positive cancers

Abstract

A radionuclide labeled UCK2-targeting compound for use in radioligand therapy and imaging of UCK2 positive cancers, such as hepatocellular carcinoma (HCC) includes a compound having the structure of formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof.

Description

UCK2- TARGETING COMPOUND FOR USE IN DETECTING AND TREATING UCK2 POSITIVE CANCERSRELATED APPLICATION

[0001] This application claims priority from U.S. Provisional ApplicationNo. 63 / 691,467, filed September 6, 2024, the subject matter of which is incorporated herein by reference in its entirety.GOVERNMENT FUNDING

[0002] This invention was made with government support under W81XWH-22-1-0784 awarded by the Department of Defense and CA204373 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Radionuclides have potential utility in cancer diagnosis and therapy, particularly if they can be delivered selectively to a target location within the body of a subject. Targeted delivery of radionuclides can be achieved by using constructs that are engineered to both securely retain the radionuclide for in vivo delivery and deliver the radionuclide selectively to a desired location within the body, with a reasonably low level of delivery to non-target regions of the body.SUMMARY

[0004] Embodiments described herein relate to a radionuclide labeled UCK2-targeting compound and its use in radioligand therapy and imaging of UCK2 positive cancers, such as renal cell carcinoma (RCC), lung squamous cell carcinoma (SQCC), and primary liver cancer hepatocellular carcinoma (HCC), as well as liver metastases from other primary cancers such as colorectal cancer. Uridine cytidine kinase 2 (UCK2) is often up-regulated as cancers (including HCC), and relocated from cytosol into nucleus as cancer progressed.

[0005] In some embodiments, a compound for use in detecting and / or treating uridinecytidine kinase 2 (UCK2) positive cancers, such as hepatocellular carcinoma (HCC), can have the structure of formula (I):pharmaceutically acceptable salt thereof; whereinL is an optional linker; andR is a radionuclide selected from18F,76Br,77Br,123I,124I,125I,131I, or211At.

[0006] In some embodiments, the optional linker can include a click chemistry linker.

[0007] In other embodiments, the optional linker can include an alkenylene or an alkynylene.

[0008] In some embodiments, where R is21’At, the compound or pharmaceutically acceptable salt thereof can be used in targeted alpha-particle therapy with synergistic Auger electron therapy of UCK2 positive cancers, such as HCC.

[0009] In some embodiments, where R is77Br, the compound or pharmaceutically acceptable salt thereof can be used for targeted beta radioligand therapy of UCK2 positive cancers, such as HCC.

[0010] In some embodiments, where R is131I, the compound or pharmaceutically acceptable salt thereof can be used for targeted beta-particle therapy of UCK2 positive cancers, such as HCC.

[0011] In some embodiments, where R is18F,76Br, or124I, the compound or pharmaceutically acceptable salt thereof can be used for targeted positron emission tomography (PET) imaging of UCK2 positive cancers, such as HCC.

[0012] In some embodiments, where R is123I, the compound or pharmaceutically acceptable salt thereof can be used for single -photon emission coupled tomography (SPECT) imaging and / or Auger electron therapy of UCK2 positive cancers, such as HCC.

[0013] Other embodiments recited herein relate to a compound having the structure of formula (III):pharmaceutically acceptable salt thereof, wherein L is an optional linker; andR1is a radionuclide selected from77Br or21'At.

[0014] Still other embodiments described herein relate to a compound having the structure of formula (IV):pharmaceutically acceptable salt thereof, wherein R1is a radionuclide selected from77Br or211At.

[0015] Other embodiments described herein relate to a compound having the structure of formula (V):pharmaceutically acceptable salt thereof.

[0016] In some embodiments, a compound having the structure of formula (III), (IV), (V) or pharmaceutically acceptable salt thereof can be used as a neoadjuvant cancer therapy or an adjuvant cancer therapy.

[0017] In some embodiments, a compound having the structure of formula (I), (III), (IV), (V) or pharmaceutically acceptable salt thereof can be synthesized from a precursor compound other than a stannyl precursor.

[0018] In some embodiments, the precursor compound can have the structure offormula (VI):wherein L is an alkenylene or an alkynylene; andR2is a boronate, boronate ester, or salt thereof, preferablypharmaceutically acceptable salt thereof.

[0019] In other embodiments, the precursor compound can be selected from:pharmaceutically acceptable salt thereof.

[0020] Other embodiments described herein relate to a method of treating a UCK2- positive cancer, such as HCC, in a subject in need thereof. The method includes administering to the subject therapeutically effective amount(s) of at least one anti-cancer agent and detecting UCK2 -positive tumor cells, such as HCC cells, in the subject using a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, where R is18F,76Br,123I, or124I.

[0021] In some embodiments, the UCK2 -positive tumor cells, such as HCC cells, are detected before and / or after administration of the anti-cancer agent.

[0022] In some embodiments, the therapeutically effective amount of the anti-canceragent is an amount effective to ablate the cancer or the target.

[0023] In some embodiments, the at least one anti-cancer agent includes a DNA methyltransferase inhibitor, such as 5-azacytidine (5-Aza) or 5-Aza-2’ -deoxycytidine alone or in combination with tetrahydrouridine (THU), other UCK2 inhibitors, or a targeted radiopharmaceutical.

[0024] In some embodiments, the method further includes administering to the subject a compound having the structure of formula (III), (IV), (V) or pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound having the structure of formula (III), (IV), (V) or pharmaceutically acceptable salt thereof is administered to the subject as a neoadjuvant therapy to sensitize the UCK2-positive cancer, such as HCC, prior to administration of the at least one anti-cancer agent or as an adjuvant therapy to kill residual cancer cells after administration of the at least one anti-cancer agent.

[0026] Other embodiments described herein relate to a method of treating a UC Expositive cancer, such as HCC, in a subject in need thereof. The method includes detecting UCK2-positive tumor cells, such as HCC cells, in the subject using a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, where R is76Br,123I, or124I. A therapeutically effective amount of at least one anti -cancer agent is administered to the subject to ablate the UCK2 -positive cancer or the UCK2 target. UCK2-positive tumor cells, such as HCC cells, are detected in the subject after administering the anti-cancer agent using a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, where R is18F,76Br,123I, or124I.

[0027] Optionally, a compound having the structure of formula (III), (IV), (V) or pharmaceutically acceptable salt thereof is administered to the subject as an adjuvant therapy after detecting the UCK2 -positive tumor cells, such as HCC cells, in the subject and after administering the anti-cancer agent.

[0028] Optionally, a compound that suppresses deoxycytidine kinase (DCK) to raise UCK2 levels, such as cloforabine (CFA), can be administered for neoadjuvant sensitization to alternatively raise UCK2 expression in cancers, such as HCC, or as a neoadjuvant sensitizer for all UCK2-targeted detection using a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, where R is18F,76Br,123I, or124I and / or therapy using a compound having the structure of formula (III), (IV), (V) or pharmaceuticallyacceptable salt thereof.

[0029] Still other embodiments described herein relate to a method of treating a cancer, such as HCC, in a subject in need thereof by administering a compound having the structure of formula (III), (IV), (V), or pharmaceutically acceptable salt thereof to the subject after detecting the UCK2-positive tumor cells, such as UCK2-positive HCC cells, in the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Fig. 1 illustrates graphs showing UCK2 is a prognostic marker for liver cancers (left). Its expression is higher in liver cancer than the surrounding hepatic tissues (right).

[0031] Fig. 2 illustrates a pair of t-SNE plots showing the results from gene sequencing of UCK2 in liver cancer (left) vs. surrounding hepatic tissues (right).

[0032] Fig. 3 illustrates UCK2 staining of liver cancer samples from two patients with HCC.

[0033] Fig. 4 illustrates graphs showing PCR results using freshly harvested woodchuck tissue samples confirmed differential expression (left). Custom woodchuck gene microarray showed similar differential expression (right).

[0034] Fig. 5 illustrates amino acid sequence blasts comparing human and woodchuck UCK2 and ENTl.

[0035] Fig. 6 illustrates graphs showing the transporter responsive for the transport of IV- 14, a uridine analog.

[0036] Fig. 7 illustrates a PET image showing stronger uptake of |124I]IV- 14 in woodchuck HCC (showing MIP, maximal intensity projection), a naturally occurring primary liver cancer in the woodchucks.

[0037] Fig. 8 illustrates [124I]IV- 14 PET imaging to monitor the treatment of HCC.DETAILED DESCRIPTION

[0038] All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified. The definitions provided herein are to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the application.

[0039] The articles "a" and "an" are used herein to refer to one or to more than one (z.<?., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0040] The terms "comprise," "comprising," "include," "including," "have," and "having" are used in the inclusive, open sense, meaning that additional elements may be included. The terms "such as", “e.g., ” as used herein are non-limiting and are for illustrative purposes only. "Including" and "including but not limited to" are used interchangeably.

[0041] The term "or" as used herein should be understood to mean "and / or" unless the context clearly indicates otherwise.

[0042] The terms “patient”, “subject”, “mammalian host,” and the like are used interchangeably herein, and refer to humans and non-human animals e.g., rodents, arthropods, insects, fish (e.g., zebrafish)), non-human primates, ovines, bovines, ruminants, lagomorphs, porcines, caprines, equines, or canines felines, aves, etc.).

[0043] The terms “cancer” or “tumor” refer to any neoplastic growth in a subject, including an initial tumor and any metastases. The cancer can be of the liquid or solid tumor type. Liquid tumors include tumors of hematological origin, including, e.g., myelomas (e.g., multiple myeloma), leukemias (e.g., Waldenstrom’s syndrome, chronic lymphocytic leukemia, other leukemias), and lymphomas (e.g., B-cell lymphomas, non- Hodgkin’ s lymphoma). Solid tumors can originate in organs and include cancers of the lungs, brain, breasts, prostate, ovaries, colon, kidneys, and liver.

[0044] The terms “cancer cell” or “tumor cell” can refer to cells that divide at an abnormal (i.e., increased) rate. Cancer cells include, but are not limited to, carcinomas, such as squamous cell carcinoma, non-small cell carcinoma (e.g., non-small cell lung carcinoma), small cell carcinoma (e.g., small cell lung carcinoma), basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, undifferentiated carcinoma, bronchogenic carcinoma, melanoma, renal cell carcinoma, hepatoma-liver cell carcinoma, bile duct carcinoma, cholangiocarcinoma, papillary carcinoma, transitional cell carcinoma, choriocarcinoma, semonoma, embryonal carcinoma, mammary carcinomas, gastrointestinal carcinoma, colonic carcinomas, bladder carcinoma, prostate carcinoma, and squamous cell carcinoma of the neck and head region; sarcomas, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synoviosarcoma and mesotheliosarcoma; hematologic cancers, such as myelomas, leukemias (e.g., acute myelogenous leukemia, chronic lymphocytic leukemia, granulocytic leukemia, monocytic leukemia, lymphocyticleukemia), lymphomas (e.g., follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, malignant lymphoma, plasmocytoma, reticulum cell sarcoma, or Hodgkin’s disease), and tumors of the nervous system including glioma, glioblastoma multiform, meningoma, medulloblastoma, schwannoma and epidymoma.

[0045] The phrases "parenteral administration" and "administered parenterally" are art- recognized terms, and include modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0046] The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, agent or other material other than directly into a specific tissue, organ, or region of the subject being treated e.g., brain), such that it enters the animal's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0047] The term “radionuclide” as used herein refers to an atom with an unstable nucleus, which is a nucleus characterized by excess energy available to be imparted either to a newly created radiation particle within the nucleus or to an atomic electron. Radionuclides occur naturally or can be artificially produced.

[0048] The terms “treating” or “treatment” of a disease can refer to executing a treatment protocol to eradicate at least one diseased cell. Thus, “treating” or “treatment” does not require complete eradication of diseased cells.

[0049] An “effective amount” can refer to that amount of a therapeutic agent that results in amelioration of symptoms or a prolongation of survival in the subject and relieves, to some extent, one or more symptoms of the disease or returns to normal (either partially or completely) one or more physiological or biochemical parameters associated with or causative of the disease.

[0050] The phrase "therapeutically effective amount" or “pharmaceutically effective amount” is an art-recognized term. In certain embodiments, the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. Tn certain embodiments, the term refers to that amountnecessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation.

[0051] Throughout the description, where compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0052] Embodiments described herein relate to a radionuclide labeled UCK2-targeting compound and its use in radioligand therapy and imaging of UCK2 positive cancers, such as renal cell carcinoma (RCC), lung squamous cell carcinoma (SQCC), and primary liver cancer hepatocellular carcinoma (HCC), as well as liver metastases from other primary cancers such as colorectal cancer (Sarkisjan, et al., PLoS ONE 2016; 11 (9):e0162901). Uridine cytidine kinase 2 (UCK2) is often up-regulated in cancers, such as HCC, and relocated from cytosol into nucleus as the cancer progresses (van Kuilenburg, et al., Biochimica el Biophysica Ada 2016;1862:1504-1512). As illustrated in Fig. 4, PCR data with harvested tissues validated this target in HCC. As illustrated in Fig. 3, IHC staining demonstrated both cytosolic and nuclear staining of UCK2 in liver cancers.

[0053] We implemented the radio-synthesis of 3’-(£')-(2-iodovinyl)uridine (IV-14), specific for positron emission tomography (PET) imaging of UCK2. IV-14 was originally derived from a UCK2-selective antitumor agent, 3’-(ethynyl)uridine, and radio-labeled with 1-131 for gamma scintigraphy of xenographic mouse models (Zlatopolskiy, et al., JNM 2009; 50: 1895-903). However, the synthesis of this radio-tracer has been difficult due to the precursor 3’-(2-E)-Tributylstannylvinyl)uridine (TBSVU). We improved upon this radiosynthesis by designing new precursors for better separation, and by labeling IV-14 with positron emitting F-18, 1-124 and Br-76 for PET imaging of HCC, and 1-123 for singlephoton emission computed tomography (SPECT) imaging. The new radionuclide labeled UCK2-targeting compound will allow us to avoid repeated liver biopsies on patients under treatment, and guide treatment selection and its rational modification, potentially before onset of clinical progression. In addition, Br-77 and At-211 are acceptable radionuclides for cancer treatment. We can therefore substitute 1-131 with Br-77 and At-211, which will turn IV- 14 into BV-14 and AV-14, respectively. [211At]AV-14 can be used for direct alpha-particle treatment that is insensitive to the common tumor resistance mechanisms and overwhelms the traditional DNA repair machinery, while [77Br]BV-14 can be used either for beta-particle therapy or for sensitizing the follow-up radio-therapy. In addition, a high dose of [123I]IV- 14 can be used for direct treatment of UCK2 positive cancers with Auger electrons.

[0054] Accordingly, in some embodiments a radionuclide labeled UCK2-targeting compound for use in detecting and / or treating uridine-cytidine kinase 2 (UCK2) positive cancers, such as UCK2-positive hepatocellular carcinoma (HCC), can have the structure of formula (I):pharmaceutically acceptable salt thereof; whereinL is an optional linker; andR is a radionuclide selected from18F,76Br,77Br,123I,124I,125I,131I, or211At.

[0055] In some embodiments, the optional linker can include a click chemistry linker, such as a succinimide linker, a maleimide linker, or an alkyne-azide linker.

[0056] In other embodiments, the optional linker can include an alkenylene or an alkynylene.

[0057] In some embodiments, R can be21'At, and the compound or pharmaceutically acceptable salt thereof can be used for targeted alpha-particle, and secondarily, Auger electron therapy (Stepanek, et al., Acta Oncol 1996;35(7): 863-868) of LJCK2 positive cancers, such as UCK2-positive hepatocellular carcinoma (HCC).

[0058] In other embodiments, R can be77Br, and the compound or pharmaceutically acceptable salt thereof can be used for targeted beta-particle, and secondarily, Auger electron therapy of UCK2 positive cancers, such as UCK2 -positive HCC.

[0059] In other embodiments, R can be123I or125I, and the compound can be used for targeted Auger electron therapy of UCK2 positive cancers, such as UCK2-positive HCC.

[0060] In still other embodiments, R can be131I, and the compound can be used mainly for targeted beta-particle therapy, and to a lesser degree, Auger therapy of UCK2 positive cancers, such as UCK2-positive HCC.

[0061] In other embodiments, R can be1SF,76Br or124I, and the compound can be used for targeted PET imaging of UCK2 positive cancers, such as UCK2-positive HCC.

[0062] In other embodiments, R can be123I and the compound is used for single-photon emission coupled tomography (SPECT) imaging of UCK2 positive cancers, such as UCK2- positive HCC.

[0063] In other embodiments, the compound can have the structure of formula (II)pharmaceutically acceptable salt thereof; wherein R is a radionuclide selected from18F,76Br,77Br,123I,124I,125I,131I, or211At.

[0064] Other embodiments recited herein relate to a compound having the structure of formula (III):(ill) or a pharmaceutically acceptable salt thereof, wherein L is an optional linker; andR1is a radionuclide selected from77Br or211At.

[0065] Still other embodiments described herein relate to a compound having thestructure of formula (IV):pharmaceutically acceptable salt thereof, wherein R1is a radionuclide selected from77Br or21 1At.

[0066] Other embodiments described herein relate to a compound having the structure of formula (V):pharmaceutically acceptable salt thereof.

[0067] In some embodiments, a compound having the structure of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof can be used as a neoadjuvant cancer therapy or an adjuvant cancer therapy.

[0068] In some embodiments, a compound having the structure of formula (I), (II), (III), (IV), (V) or pharmaceutically acceptable salt thereof can be synthesized by forming ethynyluridine from uridine (e.g., Jung et al., J. Org. Chem. 1997;62:8309-8314), reacting the ethynyluridine with a solution of tributylin hydride and Pd(PPh3)2Chto form tributylstannylvinlyuridine (TBSVU) for iododestannylation, and reacting the TBVSU with a sodium salt of a radionuclide and optional copper catalyst (Zlatopolskiy et al., JNM 2009;50: 1895-1903) as shown below.R =18F,76Br,77Br,123l,124l,125l,131l, or211At

[0069] In other embodiments, the same compounds can be synthesized from a precursor compound other than a stannyl precursor, such as tributyltin illustrated above, for better precursor separation. The other leaving groups include, but not limited to, the pinacol boronate ester (CH3)2C(OH)-C(OH)(CH3)2) for copper(II)-mediated iododeboronation (Reilly, et al., Org. Lett. 2018;20:1752-1755); Suzuki-Miyaura coupling with the pinacolato group (-(OCMe2CH2)2O) as the leaving group (Zhou, et al., J Label Compd Radiopharm. 2023;66:435-439); electrophilic iododeboronation from boronic esters and boronates (Dubost, et al., J. Org. Chem. 2020;85:8300-8310), etc.

[0070] For example, the precursor compound can have the structure of formula (VI):wherein L is an alkenylene or an alkynylene; and R2is a boronate, boronate ester, or salt thereof, preferablypharmaceutically acceptable salt thereof.

[0071] In other embodiments, the precursor compound can be selected frompharmaceutically acceptable salt thereof.

[0072] Boronic esters, boronates, or a salt thereof of ethynyluridine described above can be reacted with a sodium salt of a radionuclide and an optional catalyst, as shown below, to produce the compounds:R =18F,76Br,77Br,123l,124l,125l,1311, or211At

[0073] In some embodiments, a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof, where R is18F,76Br,124I, or123I, described herein, can be administered to a subject in a detectable quantity of a pharmaceutical composition containing the compounds. A "detectable quantity" means that the amount of the detectable compound that is administered is sufficient to enable detection of binding of the compound to the cancer cells. An "imaging effective quantity" means that the amount of the detectable compound that is administered is sufficient to enable imaging of the binding of the compound to the cancer cells.

[0074] The compound of formula (I), (II), or a pharmaceutically acceptable salt thereof, where R is18F,76Br,124I, or123I as described herein, can be administered to the subject by, for example, systemic, topical, and / or parenteral methods of administration. These methods include, e.g., injection, infusion, deposition, implantation, or topical administration, or any other method of administration where access to the tissue is desired. In one example, administration can be by intravenous injection in the subject. Single or multiple administrations of the probe can be given. “Administered”, as used herein, means provision or delivery in an amount(s) and for a period of time(s) effective to label cancer cells in the subject.

[0075] The compound of formula (I), (II), or a pharmaceutically acceptable salt thereof, where R is18F,76Br,124I, or123I described herein, administered to a subject can be used to determine the presence, location, and / or distribution of UCK2 expressing cancer cells, e.g., UCK2-positive HCC cancer cells, in liver of a patient. The presence, location, and / ordistribution of the compounds in the animal’s tissue, e.g., liver, can be visualized (e.g., with an in vivo imaging modality described above). “Distribution” as used herein is the spatial property of being scattered about over an area or volume. In this case, “the distribution of cancer cells” is the spatial property of cancer cells being scattered about over an area or volume included in the animal’s tissue, e.g., liver tissue. The distribution of the compounds may then be correlated with the presence or absence of cancer cells in the tissue. A distribution may be dispositive for the presence or absence of cancer cells or may be combined with other factors and symptoms by one skilled in the art to positively detect the presence or absence of migrating or dispersing cancer cells, cancer metastases, or define a tumor margin in the subject.

[0076] In other embodiments, the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof can be used in therapeutic applications, such as to carry out targeted radionuclide therapy. For example, the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof may be administered to a subject in any suitable manner, and the targeting effect to UCK2 can be used to deliver the radionuclide to a desired location within the subject’s body. In some embodiments, radiation from radionuclide can be used to kill UCK2 expressing cancer cells at the desired location. In some embodiments, the UCK2 expressing cancer cells that are killed at the desired location are UCK2 expressing HCC cells. In some embodiments, the compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof can be used to perform targeted radionuclide therapy. In some embodiments, the compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof can be used to perform targeted alpha therapy with synergistic Auger therapy due to nuclear relocation of UCK2.

[0077] The compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof can be administered alone as a monotherapy, or in conjunction with or in combination with one or more additional therapeutic agents. In some embodiments, the compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof described herein can be administered to the subject in combination with an additional anti-cancer agent. In a particular embodiment, the compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof as described herein can be administered to the subject in combination with anti-cancer agents, such as tetrahydrouridine (THU) and 5-azacytidine (5-Aza) or other UCK2 inhibitors that interfere or prevent the interactions between UCK2 and other proteinsand or targeted radiopharmaceutical with therapeutical intent.

[0078] The term "in conjunction with" or “in combination with” indicates that the compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof is administered at about the same time as the additional agent. The compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof can be administered to the subject in need thereof as part of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient and, optionally, one or more additional therapeutic agents. The compound and additional therapeutic agent can be components of separate pharmaceutical compositions, which can be mixed together prior to administration or administered separately. The compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof can, for example, be administered in a composition containing the additional therapeutic agent, and thereby, administered contemporaneously with the agent. Alternatively, the compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof can be administered contemporaneously, without mixing (e.g., by delivery of the compound on the intravenous line by which the compound is also administered, or vice versa). In another embodiment, the compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof can be administered separately (e.g., not admixed), but within a short timeframe (e.g., within 24 hours) of administration of the compound.

[0079] The disclosed compounds described herein and additional therapeutic agents, detectable moieties, and / or theranostic agents described herein can be administered to a subject by any conventional method of drug administration. For example, parenteral administration can include, for example, intramuscular, intravenous, intraventricular, intraarterial, intrathecal, subcutaneous, or intraperitoneal administration. The disclosed compounds can also be administered orally (e.g., in capsules, suspensions, tablets or dietary), nasally (e.g., solution, suspension), transdermally, intradermally, topically (e.g., cream, ointment), inhalation (e.g., intrabronchial, intranasal, oral inhalation or intranasal drops), transmucosally or rectally. Delivery can also be by injection into the brain or body cavity of a patient or by use of a timed release or sustained release matrix delivery systems, or by onsite delivery using micelles, gels and liposomes. Nebulizing devices, powder inhalers, and aerosolized solutions may also be used to administer such preparations to the respiratory tract. Delivery can be in vivo or ex vivo. Administration can be local or systemic, as indicated. More than one route can be used concurrently, if desired. The preferred mode ofadministration can vary depending upon the particular disclosed compound chosen. In specific embodiments, oral, parenteral, or systemic administration (e.g., intravenous) are preferred modes of administration for treatment.

[0080] The methods described herein contemplate either single or multiple administrations, given either simultaneously or over an extended period of time. The compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof (or a composition containing the compound) can be administered at regular intervals, depending on the nature and extent of the cancer, and on an ongoing basis. Administration at a "regular interval," as used herein, indicates that the therapeutically effective amount is administered periodically (as distinguished from a one-time dose). In one embodiment, the compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof is administered periodically, e.g., at a regular interval e.g., bimonthly, monthly, biweekly, weekly, twice weekly, daily, twice a day, or three times or more often a day).

[0081] The administration interval for a single individual can be fixed or can be varied over time, depending on the needs of the individual. For example, in times of physical illness or stress, or if disease symptoms worsen, the interval between doses can be decreased. Depending upon the half-life of the agent in the subject, the agent can be administered between, for example, once a day or once a week.

[0082] For example, the administration of the compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof described herein and / or the additional therapeutic agent can take place at least once on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively, at least once on week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or any combination thereof, using single or divided doses of every 60, 48, 36, 24, 12, 8, 6, 4, or 2 hours, or any combination thereof. Administration can take place at any time of day, for example, in the morning, the afternoon or evening. For instance, the administration can take place in the morning, e.g., between 6:00 a.m. and 12:00 noon; in the afternoon, e.g., after noon and before 6:00 p.m.; or in the evening, e.g., between 6:01 p.m. and midnight.

[0083] In some embodiments, the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof may be administered to the subject at an amount effective to deliver a radiation dose, for example, at or below 1 mCi / kg ( / .<?., where theamount of the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof administered to the subject delivers a radiation dose of below 1000 pCi per kilogram of subject's body weight). According to certain aspects, the effective amount is at or below 900 pCi / kg, 800 pCi / kg, 700 pCi / kg, 600 pCi / kg, 500 pCi / kg, 400 pCi / kg, 300 pCi / kg, 200 pCi / kg, 150 pCi / kg, 100 pCi / kg, 80 pCi / kg, 60 pCi / kg, 50 pCi / kg, 40 pCi / kg, 30 pCi / kg, 20 pCi / kg, 10 pCi / kg, 5 pCi / kg, or 1 pCi / kg. According to certain aspects, the effective amount of the radiation dose from the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof is at least 1 pCi / kg, 2.5 pCi / kg, 5 pCi / kg, 10 pCi / kg, 20 pCi / kg, 30 pCi / kg, 40 pCi / kg, 50 pCi / kg, 60 pCi / kg, 70 pCi / kg, 80 pCi / kg, 90 pCi / kg, 100 pCi / kg, 150 pCi / kg, 200 pCi / kg, 250 pCi / kg, 300 pCi / kg, 350 pCi / kg, 400 pCi / kg or 450 pCi / kg. According to certain aspects, the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof may be administered at an amount effective to deliver a radiation dose that includes any combination of upper and lower limits as described herein, such as from at least 5 mCi / kg to at or below 50 pCi / kg, or from at least 50 mCi / kg to at or below 500 pCi / kg.

[0084] In other embodiments, the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof may be administered to the subject at an amount effective to deliver a radiation dose and the effective amount of radiation dose delivered may be at or below 2 mCi (i.e., wherein the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof is administered to the subject in a non- weight-based dosage). According to certain aspects, the effective dose of the radiation delivered by the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof may be at or below 1 mCi, such as 0.9 mCi, 0.8 mCi, 0.7 mCi, 0.6 mCi, 0.5 mCi, 0.4 mCi, 0.3 mCi, 0.2 mCi, 0.1 mCi, 90 pCi, 80 pCi, 70 pCi, 60 pCi, 50 pCi, 40 pCi, 30 pCi, 20 pCi, 10 pCi, or 5 pCi. The effective amount of the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof may be at least 2 pCi, such as at least 5 Ci, 10 pCi, 20 pCi, 30 pCi, 40 pCi, 50 pCi, 60 pCi, 70 pCi, 80 pCi, 90 pCi, 100 pCi, 200 pCi, 300 pCi, 400 pCi, 500 pCi, 600 pCi, 700 pCi, 800 pCi, 900 pCi, 1 mCi, 1.1 mCi, 1.2 mCi, 1.3 mCi, 1.4 mCi, or 1.5 mCi. According to certain aspects, the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof may be administered at an amount effective to deliver a radiation dose that includes any combination of upper and lower limits as described herein, such as from at least 2 pCi to at or below 1 mCi, or from at least 2 pCi to at or below 250 pCi, or from 75Ci to at or below 400 pCi.

[0085] In other embodiments, the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof can be administered in a single dose that delivers less than 12Gy, or less than 8 Gy, or less than 6 Gy, or less than 4 Gy, or less than 2 Gy, such as doses of 2 Gy to 8 Gy, to the subject, such as predominantly to the targeted UCK2 expressing cancer.

[0086] In still other embodiments, the compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof may be provided in a total amount of up to or equal to 100 mg, such as up to or equal to 60 mg, such as 5 mg to 45 mg, or a total amount of from 0.001 mg / kg patient weight to 3.0 mg / kg patient weight, such as from 0.005 mg / kg patient weight to 2.0 mg / kg patient weight, or from 0.01 mg / kg patient weight to 1 mg / kg patient weight, or from 0.1 mg / kg patient weight to 0.6 mg / kg patient weight, or 0.3 mg / kg patient weight, or 0.4 mg / kg patient weight, or 0.5 mg / kg patient weight, or 0.6 mg / kg patient weight.

[0087] The amount of administered compound of formula (III), (IV), (V) or a pharmaceutically acceptable salt thereof and / or additional therapeutic agent administered to the subject can depend on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs as well as the degree, severity and type of rejection. The skilled artisan will be able to determine appropriate dosages depending on these and other factors using standard clinical techniques.

[0088] In addition, in vitro or in vivo assays can be employed to identify desired dosage ranges. The dose to be employed can also depend on the route of administration, the seriousness of the disease, and the subject's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. The amount of the compound can also depend on the disease state or condition being treated along with the clinical factors and the route of administration of the compound.

[0089] Still other embodiments described herein relate to a method of treating UCK2- positive cancers, such as UCK2-positive HCC, in a subject in need thereof by administering to the subject a radioligand therapy compound described herein.

[0090] In some embodiments, the compound of formula (III), (IV), (V), or a pharmaceutically acceptable salt thereof, or other metabolically related compounds can be used as a neoadjuvant cancer therapy or an adjuvant cancer therapy.

[0091] Other embodiments, described herein relate to a method of treating UCK2- positive cancers, such as UCK2-positive HCC, in a subject in need thereof. The method includes administering to the subject therapeutically effective amount(s) of at least one anticancer agent and detecting UCK2 -positive tumor cells, such as UCK2 -positive HCC cells, in the subject using a compound of formula (I), (II), or a pharmaceutically acceptable salt thereof, where R is18F,76Br,124I, or123I.

[0092] In some embodiments, the UCK2 -positive tumor cells, such as UCK2-positive HCC cells, are detected before and / or after administration of the anti-cancer agent, for treatment guidance, patient selection, treatment monitoring, etc.

[0093] In some embodiments, the therapeutically effective amount of the anti-cancer agent is an amount effective to ablate the cancer or the target.

[0094] In some embodiments, the at least one anti-cancer agent comprises tetrahydrouridine (THU) and 5-azacytidine (5-Aza).

[0095] In some embodiments, the anti-cancer agent includes a compound that suppresses deoxycytidine kinase (DCK) to raise UCK2 levels, such as cloforabine (CFA), for neoadjuvant sensitization.

[0096] In some embodiments, the method further includes further administering to the subject a compound of formula (III), (IV), (V), or pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the compound of (III), (IV), (V), or pharmaceutically acceptable salt thereof or other compounds, such as clofarabine (CFA), is administered to the subject as a neoadjuvant therapy to sensitize the HCC prior to administration of the at least one anti-cancer agent or as an adjuvant therapy to kill residual cancer cells after administration of the at least one anti-cancer agent.

[0098] Still other embodiments relate to a method of treating UCK2 -positive cancers, such as UCK2-postive HCC, in a subject in need thereof. The method includes detecting UCK2-positive tumor cells, such as UCK2 -positive HCC cells, in the subject using a compound of formula (I) or a pharmaceutically acceptable salt thereof, where R is18F,76Br,124I, or123I. After detecting the UCK2-positive tumor cells, such as UCK2 -positive HCC cells, in the subject, therapeutically an effective amount(s) of at least one anti-cancer agent, such as tetrahydrouridine (THU) and 5-azacytidine (5-Aza), or other compounds that interfere or prevent interactions between UCK2 and other proteins can be administered to the subject to inhibit the progression of UCK2-positive cancers, such as UCK2-positive HCC.Following administration of the therapeutically effective amount(s) of at least one anti-cancer agent, such as THU and 5-Aza, remaining or residual UCK2-positive tumor cells, such as UCK2-positive HCC cells, in the subject can be detected using a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is18F,76Br,124I, or123I, to determine or monitor the efficacy of the at least one anti-cancer agent(s), such as THU and 5-Aza. Optionally, a compound having structure of formula (III), (IV), (V), or pharmaceutically acceptable salt thereof can be administered to the subject as an adjuvant therapy after detecting the UCK2-positive tumor cells, such as UCK2-positive HCC cells, in the subject and after administering the at least one anti-cancer therapy, such as THU and 5-Aza, or a targeted radiopharmaceutical for therapy.Example

[0099] Fig. 1 illustrates graphs based on TCGA data showing UCK2 is a prognostic marker for liver cancers (left). Its expression is higher in liver cancer than the surrounding hepatic tissues (right).

[0100] Fig. 2 illustrates a pair of t-SNE plots showing the results from single-cell RNA- sequencing (scRNA-seq) of UCK2 in human liver cancer (left) vs. surrounding hepatic tissues (right), the raw data from GSE125449.

[0101] Fig. 3 illustrates IHC (brown) staining of UCK2 with liver cancer tissue samples from two patients with HCC with hematoxylin (blue) nuclear counterstain showing both cytosolic and nuclear staining.

[0102] Fig. 4 illustrates graphs showing PCR results using freshly harvested woodchuck tissue samples confirmed differential expression (left). Custom woodchuck gene microarray showed similar differential expression (right), the raw data from GSE36545.

[0103] Fig. 5 illustrates amino acid sequence blasts comparing human and woodchuck UCK2 and ENT 1. The sequence blasts show high homology between human and woodchuck (marmota) for both UCK2 and ENT1 with identical key amino acid residues (colored) involved in substrate binding. This confirms that the woodchuck model of HCC is authentic to the corresponding human disease when both the imaging / therapeutic target UCK2 and transporter ENT1 for the radiopharmaceutical are highly homologous between human and woodchuck.

[0104] Fig. 6 illustrates graphs showing the expression of the main transporter (ENT1) responsible for the transport of IV- 14, a uridine analog, into both cytosol and nucleus.Among them the equilibrative nucleoside transporters (ENTs) are the diffusion-limited channels with 11 transmembrane domains and usually transport substrates down concentration gradients. ENT1 has a higher affinity for uridine and its analogues than ENT2, and abundant on both plasma membrane and nuclear envelope (Hau, et al., Clin Pharmacol Ther. 2023;l 14(4):780-794). As illustrated in Fig. 5, ENT1 is highly preserved between the species showing a high homology between the human and woodchuck. ENT1 expression is higher in human HCC than in the hepatic tissue (from TCGA), which is echoed by PCR of woodchuck tissues (right).

[0105] Fig. 7 illustrates a PET image showing stronger uptake of [124I]IV- 14 woodchuck HCC (showing MIP, maximal intensity projection), a naturally occurring primary liver cancer in the woodchucks. [124I]IV- 14 was stable in vivo demonstrated by little thyroid or stomach signal (endogenous NIS expression) by 60 min post-injection indicating little dehalogenation.

[0106] Fig. 8 illustrates [124I]IV- 14 PET imaging to monitor the treatment of HCC,. Baseline scan showed high uptake in HCC. After 6 weeks of treatment of THU + 5-Aza, tumor uptake is almost gone (red-cross) with no background uptake. PET / CT showed uniform abdominal region, and the animals are gaining weight.

[0107] From the above description of the invention, those skilled in the art will perceive improvements, changes and modifications. Such improvements, changes and modifications within the skill of the art are intended to be covered by the appended claims. All references, publications, and patents cited in the present application are herein incorporated by reference in their entirety.Sarkisjan D, Julsing JR, Smid K, et al. The Cytidine Analog Fluorocyclopentenylcytosine (RX-3117) Is Activated by Uridine-Cytidine Kinase 2. PloS one 2016; 11(9): e0162901. van Kuilenburg AB, Meinsma R. The pivotal role of uridine-cytidine kinases in pyrimidine metabolism and activation of cytotoxic nucleoside analogues in neuroblastoma. Biochimica et biophysica acta 2016; 1862(9): 1504-12. Stepanek J, Larsson B, Weinreich R. Auger-electron spectra of radionuclides for therapy and diagnostics. Acta Oncol 1996; 35(7): 863-8. Jung PM, Burger A, Biellmann JF. Diastereofacial Selective Addition of Ethynylcerium Reagent and Barton-McCombie Reaction as the Key Steps for the Synthesis of C-3'-Ethynylribonucleosides and of C-3'-Ethynyl-2'- deoxyribonucleosides. J Org Chem 1997; 62(24): 8309-14. Zlatopolskiy BD, Morgenroth A, Kunkel FH, et al. Synthesis and biologic study of IV- 14, a new ribonucleoside radiotracer for tumor visualization. J Nucl Med 2009; 50(11): 1895-903. Reilly SW, Makvandi M, Xu K, Mach RH. Rapid Cu-Catalyzed [(21 l)At]Astatination and [(125)I]Iodination of Boronic Esters at Room Temperature. Org Lett 2018; 20(7): 1752-5. Zhou D, Chu W, Xu J. A practical protocol for large-scale copper-mediated radioiodination of organoboronic precursors: Radiosynthesis of [(123) I]KX-1 for Auger radiotherapy. J Labelled Comp Radiopharm 2023; 66(13): 435-9. Dubost E, McErlain H, Babin V, Sutherland A, Cailly T. Recent Advances in Synthetic Methods for Radioiodination. J Org Chem 2020; 85(13): 8300-10. Hau RK, Wright SH, Cherrington NJ. Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development. Clin Pharmacol Ther 2023; 114(4): 780-94.

Claims

Having described the invention, the following is claimed:

1. A compound for use in detecting and / or treating uridine-cytidine kinase 2 (UCK2) positive cancers, such as hepatocellular carcinoma (HCC), having the structure of formula (I):pharmaceutically acceptable salt thereof; whereinL is an optional linker; andR is a radionuclide selected from18F,76Br,77Br,123I,124I,125I,131I, or211At.

2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the optional linker includes a click chemistry linker.

3. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the optional linker includes an alkenylene or an alkynylene.

4. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 3, wherein R is21'At.

5. The compound or pharmaceutically acceptable salt thereof of claim 4, for use in targeted alpha-particle therapy with synergistic auger electron therapy of UCK2 positive cancers, such as HCC.

6. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 3, wherein R is77Br.

7. The compound or pharmaceutically acceptable salt thereof of claim 6, for use in targeted beta radioligand therapy of UCK2 positive cancers, such as HCC.

8. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 3, wherein R is131I, for use in targeted beta-particle therapy of UCK2 positive cancers, such as HCC.

9. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 3, wherein R is18F,76Br, or124I, for use in targeted positron emission tomography (PET) imaging of UCK2 positive cancers, such as HCC.

10. The compound or pharmaceutically acceptable salt thereof of any of claims 1 to 3, wherein R is123I, for use in single-photon emission coupled tomography (SPECT) imaging and / or Auger electron therapy of UCK2 positive cancers, such as HCC.

11. A compound having the structure of formula (III):pharmaceutically acceptable salt thereof, wherein L is an optional linker; andR1is a radionuclide selected from77Br or21'At.

12. A compound having the structure of formula (IV) :pharmaceutically acceptable salt thereof, wherein R1is a radionuclide selected from77Br or21 1At.

13. A compound having the structure of formula (V):pharmaceutically acceptable salt thereof.

14. The compound or pharmaceutically acceptable salt thereof of any of claims 11 to 13, for use as a neoadjuvant cancer therapy or an adjuvant cancer therapy.

15. A compound or pharmaceutically acceptable salt thereof of any of claims 1 to 14 synthesized from a precursor compound other than a stannyl precursor.

16. The compound or pharmaceutically acceptable salt of claim 15 thereof, synthesized from a precursor compound having the structure of formula (V):wherein L is an alkenylene or an alkynylene; andR2is a boronate, boronate ester, or salt thereof, preferablythereof.

17. The compound or pharmaceutically acceptable salt of claim 15 or 16, wherein the precursor compound is selected from18. A method of treating a UCK2-positive cancer, such as HCC, in a subject in need thereof, the method comprising: administering to the subject therapeutically effective amount(s) of at least one anti-cancer agent; and detecting UCK2-positive tumor cells, such as HCC cells, in the subject using a compound of claim 9 or claim 10.

19. The method of claim 18, wherein the UCK2 -positive tumor cells, such as HCC cells, are detected before and / or after administration of the anti -cancer agent.

20. The method of claim 18 or 19, wherein the therapeutically effective amount of the anti-cancer agent is an amount effective to ablate the cancer or the target.

21. The method of any of claims 18 to 20, wherein the at least one anti-cancer agent comprises a DNA methyltransferase inhibitor, such as 5-azacytidine (5-Aza) or 5-Aza-2’ -deoxy cytidine, alone or in combination with tetrahydrouridine (THU), other UCK2 inhibitors, or a targeted radiopharmaceutical.

22. The method of any of claims 18 to 21 , further comprising administering to the subject a compound of any of claims 11 to 13.

23. The method of claim 22, wherein the compound of any of claims 11 to 13 is administered to the subject as a neoadjuvant therapy to sensitize the UCK2-positive cancer, such as HCC, prior to administration of the at least one anti-cancer agent or as an adjuvant therapy to kill residual cancer cells after administration of the at least one anti-cancer agent.

24. A method of treating a UCK2-positive cancer, such as HCC, in a subject in need thereof, the method comprising: detecting UCK2-positive tumor cells, such as HCC cells, in the subject using a compound of claim 9 or 10; administering to the subject therapeutically effective amounts of at least one anti-cancer agent to ablate the UCK2 -positive cancer or the target; detecting UCK2-positive tumor cells, such as HCC cells, in the subject after administering the anti-cancer agent using a compound of claim 9 or claim 10; optionally administering the compound of any of claims 11 to 13 to the subject as an adjuvant therapy after detecting the UCK2 -positive tumor cells, such as HCC cells, in the subject and after administering the anti-cancer agent; and optionally administering a compound that suppresses deoxycytidine kinase (DCK) to raise UCK2 levels, such as clofarabine (CFA), for neoadjuvant sensitization to alternatively raise UCK2 expression in cancers, such as HCC, as a neoadjuvant sensitizer for all UCK2-targeted detection using a compound of claim 9 or claim 10 and therapy using a compound of any of claims 11 to 13.

25. A method of treating a cancer, such as HCC, in a subject in need thereof, the method comprising:administering the compound of any of claims 11 to 13 to the subject after detecting the UCK2-positive tumor cells, such as HCC cells in the subject; and optionally administering a compound that suppresses deoxycytidine kinase (DCK) to raise UCK2 levels, such as clofarabine (CFA), for neoadjuvant sensitization or to raise UCK2 expression in cancers, such as HCC, as a neoadjuvant sensitizer for UCK2- targeted detection using a compound of claim 9 or claim 10 and therapy using a compound of any of claims 11 to 13.

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