Theranostics for cancer therapy

1. Introduction

Some of the challenges in cancer therapeutics include heterogeneity, resistance and micrometastasis of cancers making them unsuitable for surgery or radiotherapy.? Therefore, it is imperative that we have a better understanding of these tumors so that the success rate of these treatments can be improved. In this regard, theranostics could be one of the best bets in the field of precision medicine, where tumors with expression of a selected biomarkers can be identified and selectively treated by the theranostic agent. Theranostics refers to the use of radionuclides for imaging (diagnosis) as well as therapy, and as the name suggests, combines diagnostics and therapeutics. Once a theranostic agent is administered to the patient, it can then be visualized by imaging using various techniques such as SPECT, PET, MRI, florescence imaging, etc. These visualizations help us in diagnosing, staging the disease as well in assessing the therapeutic efficacy of the theranostic agent. Other than radionuclides, fluorescence and photoacoustic based imaging agents are also being evaluated for diagnostics while chemotherapeutic drugs, photothermal/dynamic therapies are also considered for therapeutics. Main focus of this article is on radionuclide based theranostic approaches.

Basic concept:

Currently used theranostic agents target a cell surface protein on cancer cell, bind to the target and get internalized thereby permitting imaging as well as therapy. Radionuclides are typically attached to a ligand (small molecule, peptide or antibody) through a linker and in turn the ligand binds to a specific cell surface target that is unique to the cancer cell (Fig. 1). Once bound, the radioligand is internalized into the cell that expresses the target and accumulates in the cell leading to effective visualization. The radioactive decay of the radioligand by release of electrons leads to selective DNA damage and cell death.

Typically, the choice of the radionuclide is based on the serum half-life of the ligand that is being used. For PET imaging, the radioisotopes fluorine‐18 (18F) or gallium‐68 (68G) or lutetium‐177 (177L) are commonly used with small molecules while zirconium‐89 (89Zr) is being increasingly used with antibodies. As therapeutic radioisotope, iodine‐131 (131I) was being widely used with antibodies, until recently, whereas currently lutetium‐177 (177L) has become the most favoured radioisotope.

2. Target proteins ligands:

Monocloncal antibodies (mAb) or peptide/small molecules are typically used to deliver a chemotherapy agent or a radioactive isotope as a payload. Some of the cellular targets that have been heavily exploited for theranostic use are somatostatin receptors (SSR) and prostate specific membrane antigen (PSMA). Others include Her2 (trustuzumab), Vascular endothelial growth factor (VEGF, bevacizumab), epidermal growth factor receptor (EGFR, lumretuzumab) and immune checkpoint proteins (PD-1/PD-L1, atezolizumab).

Antibody based targeting:

mAbs have a longer half-life of few weeks in the body and several radionuclides such as 123I and 111In for SPECT and 64Cu, 124I, 86Y and 89Zr for PET imaging have been used with mAbs. Studies have shown that these agents can accurately and non-invasively select the right population for the treatment; still these are being used as companion diagnostics and for palliative treatment and not as sole therapeutic agents. Despite the promise, antibody based agents are not preferred for routine clinical use because of the low clearance/longer half-life, which leads to deposition in organs and subsequent lower tumor-to-background ratio.

To overcome the drawbacks of the mAbs, non-covalent scFv multimers and heavy chain antibodies (hcAb) are being evaluated that retain the antigen-binding affinity of the antibody and yet are cleared from the system more efficiently. Therefore, while they are quite useful for imaging, still not efficacious enough for therapeutic use. Here, the key is in finding something optimal with good affinity and sufficient serum half-life.

Non-antibody based targeting:

SSR, particularly SSR2a, expressing neuroendocrine tumors (NETs) of the pancreas and midgut are targeted with antagonist DOTA peptides (DOTATATE: tetraazacyclododecane tetraacetic acid octreotate) for imaging (68Ga) or with theranostic pair (177Lu-DOTA-peptides or yttrium 99 octreotate) for therapy. Similarly, peptide motif Glu-NH-OH-NH-Lys is used for targeting PSMA in prostate cancers that overexpress this cell surface protein.

Following are the two approved theranostic agents 177Lu‐DOTATATE (Lutathera) and 177Lu–PSMA‐617 (Pluvicto) from Novartis Pharmaceuticals. In the pivotal Neuroendocrine Tumors Therapy (NETTER)–1 phase 3 trial 177Lu-DOTATATE (Fig. 2a) demonstrated increased progression-free survival (at 20 months of 65.2% versus 10.8% in the control), as well as a significantly increased tumor response rate in patients with advanced midgut NETs and was approved by FDA in 2018.

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177Lu-PSMA-617 (Fig. 2b), was approved recently based on increased progression free survival and overall median survival of metastatic castration resistant prostate cancer patients in the phase 3 VISION trial. 177Lu-PSMA-617 targets PSMA on prostate cancer cells and recent clinical trials are investigating the effect of this agent in neovascular expression of PSMA in glioblastoma, thyroid cancer, and hepatocellular carcinoma.

To cast the net wider, some of the newer targets Bombesin family G protein–coupled receptor, C-X-C chemokine receptor type 4 (CXCR-4), neurotensin receptor 1 (NTR1), Fibroblast activation protein (FAP) and six transmembrane epithelial antigens of the prostate 1, or STEAP1 are being investigated in clinical trials.

3. Radioligands:

?The type of radiation emitted by a radionuclide is critical in understanding its therapeutic potential. There are mainly α, β and Auger emitting radioisotopes that have been used in theranostics. β-emitting radionucleotides are the most commonly used primarily owing to their availability. β-emission occurs in radionuclides with an excess neutron that undergoes β-minus decay. β Particles have a negative charge and low linear energy transfer (LET, approximately 0.2 keV/μm) and therefore less likely to cause cytotoxicity or immunogenic effect; they have a long travel distance of approximately 2–12 mm (20 to 120 cell lengths) and therefore more likely to cause injury to healthy cells. Auger electrons are a type of β-emitters with low-energy electrons emitted by radionuclides when they decay by electron capture. Auger electrons travel an extremely short distance, in the nanometer to micrometer range

On the other hand, an α particle is positively charged and is almost three orders of magnitude bigger than a β particle. As a result, α particles have a much higher LET (80 keV/μm) compared to β particles and therefore more likely to cause cytotoxicity and immune activation; but they travel a much shorter distance of 50–100 μm (one to three cell lengths) thereby limiting off-target effects. Accordingly, several newer α-emitting particles Actinium 225, (225Ac), Astatine 211, (211At), Bismuth 213, (213Bi), Lead 212 (212Pb) Thorium 227 (221Th) are being investigated in clinical trials. Based on the approval of 177Lu-PSMA-617, 225Ac–PSMA‐617 is undergoing trials and has been reported to be effective and a well-tolerated treatment option for patients with mCRPC.

4. Non-targeted radionuclides:

Radioisotopes of sodium, 131I, 123I, 124I have long been used in the diagnosis and treatment of thyroid cancer purely based on uptake of iodine by the thyroid gland. But, based on several retrospective studies looking at iodine accumulation, iodine isotopes are now being evaluated in pheochromocytoma, paraganglioma and neuroblastoma. 131I-metaiodobenzylguanidine (131I MIBG), for example is used for treatment while 123I-MIBG is used for diagnosis of thyroid cancer. Similarly, bone metastasis of prostate cancer can be imaged with 99mTc-medronate or fluorine 18 (18F)–sodium fluoride and treated with radium 223–dichloride (223RaCl2) or strontium 89–chloride (89SrCl). These agents do not target the cancer cells, but the mimic calcium and have increased affinity to hydroxyapatite at sites of enhanced bone turnover, thereby getting absorbed into the bone. 223RaCl2 and 131I-MIBG have been approved for therapeutic use.

5. Combination therapies:

Combination therapies are being considered to expand and maximize the use of radionuclides in cancer therapy. Use of α-radiation emitter in cancers that are resistant to or progressed on β-emitters and use of low dose chemotherapies to augment the effect of radiation are some of the approaches that are being evaluated. Several combination therapies are being assessed with 177Lu-PSMA-617 in metastatic prostate cancer and hormonal therapy (Enzalutamide), DNA-damage or apoptosis inducing (PARP inhibitor or Idranoxil) and immune checkpoint inhibitor (Pembrolizumab) combinations have shown promising initial results in the clinic. Similarly, in neuroendocrine tumors the combination of 177Lu-DOTATATE and capecitabine or temozolamide have shown good tolerability as well as prolonged survival.

6. Challenges:

The use of radioactive substances is highly regulated and obtaining/using them is occasionally challenging due reactor or theranostic center compatibility or unavailability. For successful implementation of theranostic concepts into patient care multiple aspects need to be addressed, including training of professional, modifying the standard protocols, incorporation of nuclear medicine expert in the tumor boards and establishing clear protocols for reimbursements.

Also, current dose limits based on normal organ doses need to be re-considered so that the theranostic agents can be administered at the right doses to achieve therapeutic responses. Another important aspect is personalized dosimetry based therapy, which is currently not being adopted in clinical practice. Dosimetry is likely to have a promising role in modulating further dose regimens and in predicting patients likely to respond. Therefore, concerted efforts need to be put in this direction to establish the impact of dosimetry on patient outcomes.

7. Conclusion:

Radiotheranostics is a promising rapidly developing field that has changed the landscape for thyroid, neuroendocrine, and prostate tumors. In addition to addressing the financial and logistic challenges, evaluating newer molecular targets, combination approaches, use of more effective α-radiation emitters and dosimetry studies have the potential to expand the field of theranostics into broader and more effective applications in cancer therapy.

References:

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3.????? Burkett et al.,? A Review of Theranostics: Perspectives on Emerging Approaches and Clinical Advancements. Radiology: Imaging Cancer 2023; 5(4):e220157

4.????? Waaijer et al., Molecular Imaging in Cancer Drug Development. J Nucl Med 2018; 59:726–732

5.????? Gomes Marin et al., Theranostics in Nuclear Medicine: Emerging and Re-emerging Integrated Imaging and Therapies in the Era of Precision Oncology. RadioGraphics 2020; 40:1715–1740