Abstract
Glioblastoma multiforme (GBM), the most common primary brain tumour, is also the most aggressive neoplasm in the brain. It is characterized by a very poor prognosis with a median overall survival time of only 9–15 months. The infiltrating nature of the tumour cells, inter- and intra-tumoral molecular heterogeneity and the tumour’s propensity to hide behind the blood-brain barrier are the key causes of the insufficiency of the optimal available treatments (surgery, radiotherapy and chemotherapy). Furthermore, the best treatment strategy for patients with recurrent GBM remains uncertain and controversial yet. Despite applying state-of-the-art treatments in the majority of patients, the recurrence of the disease is common and the median survival after recurrence is 8.0–9.8 months. In order to avoid treatment insufficiencies, precision medicine-based therapeutics have emerged. An alternative method of treatment is targeted radionuclide therapy, which targets tumour-specified molecules on the surface of tumour cells. It has been shown that brain tumours overexpress several peptides on their surface, which may or may not be immunologically active, that can be used as a biologic target for the therapy. Radionuclide therapy involves the coupling of a peptide, which targets tumour-specific peptides, with a radionuclide payload to selectively irradiate tumour cells with negligible damage to the adjacent healthy tissue. This chapter discusses the use of radiolabelled conjugates for the treatment of brain tumours.
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10.1 Introduction
Malignant brain neoplasms are generally classified into primary neoplasms and metastatic tumours. The former originate from the brain parenchyma itself and the latter arise from body systems other than the brain. Primary brain tumours are typically sorted based on the WHO classification (2016) into glioma tumours and meningiomas as the most frequent tumours, and other less frequent tumours [1]. Tumour recurrence is usually inevitable in about 90% of patients, and then, regardless of frontline treatment strategies, the prognosis is less than 6 months.
Metastatic brain tumours usually originate from lung, breast and skin (melanoma) tumours, respectively. The overall survival duration for patients with glioblastoma multiforme (GBM) usually ranges between 14.6 and 16.8 months, with a 24-month overall survival rate of 27–30% [2,3,4].
Although the prevalence rate of brain tumours is slightly increased, the disease prognosis is still impoverished, particularly for high-grade tumours [3, 5].
The optimal treatment for brain tumours includes surgical resection and chemoradiotherapy in the routine clinical setting. However, patients show variable responses to the currently available treatments and many new therapeutics fail to show effective therapeutic response in the clinical trial phase; thus, prognosis still remains poor and an effective treatment is lacking. The causes underlying the different treatment responses include the development of compensatory resistance/escape pathways, pharmacodynamic failure (no therapeutic effect despite sufficient drug activity on the target), pharmacokinetic failure (inadequate dose delivery to the tumour), the barricading function of the blood-brain barrier (BBB) and most importantly, the inter- and intra-tumoral heterogeneity that both allow the tumour cells to resist an across-the-board treatment strategy. In addition, the infiltrative property of the tumours leads to recurrence at or adjacent to the primary site of the tumour following each surgery, so that complete resection of the tumour is impossible [6]. Thus, an across-the-board treatment is ineffective in treating these complex and heterogeneous tumours of the brain.
The prerequisites for dealing with these tumours involve providing a tailored treatment by delivering the right drug to the right patient based on individual molecular and genetic characteristics; precision medicine seems to be a key solution. Precision medicine can provide a tailored treatment in order to meet the unsatisfied essentials for the treatment of brain tumours. In the context of neuro-oncologic care, the precision medicine concept is epitomized by target-based therapeutic approaches such as peptide receptor radionuclide therapy (PRRT) and radioimmunotherapy (RIT).
In detail, RIT involves the administration of a coupling of a radionuclide payload and a monoclonal antibody (mAb) that targets the cell-surface tumour-related antigens or the antigens within the tumour microenvironment [7]. This chapter aims to discuss the biologic targets used in the PRRT and RIT approach in brain tumours treatment and to highlight recent progress in radionuclide-based pharmaceutics and clinical trials. Finally, we provide perspectives and directions on the future PRRT and RIT in neuro-oncology cancer care. The substantial characteristics of ideal therapeutic radiopharmaceutical and available radiotracer for brain tumour imaging are shown in Tables 10.1 and 10.2, respectively.
10.1.1 Radionuclides Used in the Therapy
The therapeutic effect of radionuclide therapy depends on two radiobiologic properties: range and energy. Each of these parameters has a fundamental role in the processes inducing cell death. Two types of radionuclides are usually utilized: beta (131I, 90Y, 177Lu) and alpha emitters (225Ac, 213Bi). The general properties of radionuclides for cancer therapy and the parameters affecting the uptake of radiopharmaceuticals in glioma tumours are summarized in Tables 10.3 and 10.4, respectively.
10.1.1.1 Alpha-Emitter Radionuclide
Alpha-emitting radionuclides have valuable advantages for use in targeted therapy. Alpha particles have a short range of <100 μm and a high level of linear energy transfer (LET ≈ 100 keV/μm) in human tissue. These features enable this radionuclide to deliver a critical cytotoxic dose to the targeted tumour cells while minimizing damage to the adjacent healthy tissues. Furthermore, cell death induced by alpha radiation is predominantly related to DNA double-strand breaks occurring along the trajectory of the profoundly ionizing particle and is mainly independent of both the phase of cell cycle and cellular oxygenation status [10, 11].
Moreover, it has been documented that alpha radiation is able to break the tumour’s resistance to chemotherapeutics and irradiation (beta and gamma radiation) [12]; thus, targeted alpha therapy can provide an alternative option for the treatment of patients whose disease is refractory to standard therapies. It needs to be emphasized that the effect of radiation is not dependent on O [6]-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, the most important predictive for the efficacy of treatment with temozolomide. Moreover, alpha-emitter particles perform better than temozolomide in vitro in treating multiple GBM cell lines as well as GBM stem cells (GSCs) [13].
225Ac is an alpha emitter with a half-life of 9.9 days. The main decay path of 225Ac comprises four net alpha-emitter particles with a high cumulative energy of 28 MeV and two beta-emitters of 1.6 and 0.6 MeV maximum energy. Gamma emissions are also produced in the 225Ac decay path, allowing for limited in vivo imaging. Its relatively long half-life of 9.9 days and its multi-alpha particles emission in a rapid decay chain have made 225Ac a critical cytotoxic radionuclide.
213Bi is a hybrid alpha/beta emitter with a half-life of 46 minutes. It predominantly decays by beta emission to the very short-lived absolute alpha emitter 213Po (T1/2 = 4.2 μs, E = 8.4 MeV) with a disintegration ratio of 97.8%. The residual 2.2% of 213Bi decays into 209Tl by emitting an alpha particle (E = 5.5 MeV, 0.16%, E = 5.9 MeV, 2.01%). The alpha particle emitted by 213Po has an energy of 8.4 MeV and a path length of 85 μm in body tissues [14]. A summary of a-emitter particles used in the treatment of brain tumours is listed in Table 10.5.
10.1.1.2 Beta-Emitter Radionuclide
Currently, radionuclide therapy in human cancer therapy is mainly based on energetic β-emitting particles. These β-particles are negatively charged electrons emitted from the nucleus during the decaying process of radioactive atoms and have different energies and a spectrum of ranges. After emission, as these β-particles pave their path, they lose their kinetic energies and finally take a contorted path and then stop. The recoil energy of the daughter nucleus is negligible due to its small mass [8]. The β-particle emission decayed by the beta-emitters has a maximum kinetic energy of 0.3–2.3 MeV and a penetration range of ~0.5–12 mm in soft tissue [17].
The β-particles range/cell diameter ratio enables β-particles to traverse the cells (10–1000). An important implication of the long range of the emitted electron is the cross-the-fire effect, a condition in which the radiation beam can irradiate the cells near the targeted cell without direct binding to those cells. A summary of beta-emitter particles used in the treatment of brain tumours is presented in Table 10.6.
10.1.2 Routes of Drug Administration
10.1.2.1 Systemic Administration of Radioconjugates
Typically, the systemic administration of therapeutics to treat various solid neoplasms ensures the delivery of a therapeutic dose to the tumour tissue; however, brain tumours represent an exception. Systemic drug application to brain tumours is restricted by several limitations, of which the most substantial is the intact BBB which prevents the distribution of drugs within the brain tissue. Nonetheless, the systemic administration of radiolabelled monoclonal antibodies (mAbs) via RIT approach for the treatment of brain tumours is possible in principle.
For instance, Emrich et al. attained an encouraging response following the intravenous (iv) administration of 125I-labeled EGFR-mAb 425 for the treatment of patients with high-grade glioma tumours [20]. Another study compared the uptake of radioconjugates in tumours and demonstrated that, following the iv injection of radioconjugates, the levels of 131I-labeled 81C6 (tumour-specific mAbs) were five times greater than those of co-injected 125I-labeled 45.6 (tumour non-specific mAbs). These results were post-therapeutically controlled by a histological examination of tissue biopsies. Furthermore, Zalutsky et al. concluded that the level of 131I-labelled 81C6 was up to 200 times greater than that in normal brain tissue based on the biopsies [21]. Remarkably, they studied the tumour dose delivery of the mAbs to the glioma tumours after iv and intra-carotid administration of a radiolabelled-mAb. They found that there is no significant difference in drug delivery between iv and intra-carotid application of the radiolabelled-mAb, but that the intra-carotid injection may be associated with carotid cannulation-related complications.
10.1.2.2 Locoregional Application of Radioconjugates
The locoregional application of the therapeutic is defined as the direct injection of a radiolabelled-mAb either in the tumoral tissue, a tumour cyst or a surgically created resection cavity (SCRC). This method is the best of choice for drug delivery to brain tumours, mainly because it can circumvent the BBB, the most important physical barrier impeding drug penetration into the brain tissue. Other benefits of locoregional application include its capacity to deliver a high dose of radiation to the tumour while minimizing systemic toxicity and interference with potential human antibodies against mouse antigen (HAMA). Locoregional administration of the therapeutic is done either via convection-enhanced delivery (CED) or Ommaya reservoir [22].
The CED method involves the implantation of a catheter through which therapeutic products can be applied using constant, low, positive pressure bulk flow. Pre-clinical and clinical investigations have revealed that CED can provide effective therapeutic delivery to substantial volumes of the brain and brain tumour. However, catheter technology has several shortcomings that impede the technique from being reliable and reproducible as will be discussed below. Furthermore, the only completed phase III study of GBM did not demonstrate a survival advantage for patients treated with a trial therapeutic administered via CED. Although many ongoing efforts have been made to implement innovative catheter designs and imaging approaches, there is still a long way to go to introduce an effective locoregional drug delivery system [23].
10.2 Peptide Receptor Radionuclide Therapy
10.2.1 Biologic Targets for PRRT
10.2.1.1 Neurokinin Type 1 Receptor
Neurokinin type 1 (NK-1R) is one of three different types of mammalian tachykinin receptors that belong to the seven transmembrane G-protein-coupled receptor family. NK-1R applies its effect by activating phospholipase C, then producing inositol triphosphate [24]. The ligand for NK-1R is substance-P (SP) [25]. Furthermore, the overexpression of NK1-R in glioma tumours has provided a basis for NK-1R-targeted therapy for the treatment of brain tumours. So far, the administration of 225Ac-DOTA-substance-P has shown promising results in pre-clinical studies [13]. Also, Królicki et al. reported promising results for using 213Bi-DOTA-substance P in recurrent GBM [26].
10.2.1.2 Glioma Chloride Channels
A chloride ion channel was found to be ubiquitously expressed in glioma tumours while lacking in normal brain tissue [27]. Also, the expression level of glioma chloride channel (GCC) is related to the tumour grade, such that 90% or more of high-grade gliomas and all GBMs express GCC [27]. Therefore, GCC can be used either as a diagnostic biomarker or as a target for therapy. Chlorotoxin (CTX) is a 36-amino acid protein that is isolated from the venom of the giant yellow Israeli scorpion (Leiurus quinquestriatus); it effectively inhibits the molecular currents passing through the GCC with approximately 80% effectiveness [27].
TM-601 is an artificial form of CTX and is a lyophilized, sterile and pyrogen-free compound. 131I-TM-601 comprises TM-601 as a targeting component coupled with 131I as a radionuclide payload [28]. This radiolabelled therapeutic is approved for phase I of clinical trials and the results are promising to start phase II.
10.2.1.3 Somatostatin Receptor
The peptide somatostatin is excreted by the endocrine, neural and immune systems and is ubiquitously expressed by several tissues of the body. Its functions include neuroregulation (motor, sensory and cognition) and cellular growth blockage by paracrine and autocrine routes [29, 30]. Somatostatin function is induced through transmembrane G protein-coupled receptors; the molecule enters the cell after binding to the ligand [31]. To date, six subclasses of somatostatin receptors (SSTRs) have been found: SSTR 1, 2A, 2B, 3, 4 and 5.
Many brain tumours express different subclasses of SSTR on their cell surface; these include primary brain neoplasms such as glioma tumours, meningioma neoplasms, paediatric tumours of the brain (medulloblastomas), pituitary adenomas and supratentorial primitive neuroendocrine tumours (PNETs) [32,33,34,35]. Dutour et al. [36] revealed that glioma and meningioma tumours express at least one, and sometimes different multiple subclasses of SSTR. They provided the proofs on identifying SSTRs in tumours and the surrounding tissues, predominantly in the blood vessels related to tumour neovascularization.
So far, three 68Ga-DOTA peptides have been produced for clinical imaging; these include 68Ga-DOTA-TOC, 68Ga-DOTA-NOC and 68Ga-DOTA-TATE. The ability to bind to SSTR2 is the common characteristic of 68Ga-DOTA peptides, but they differ in terms of their SSTR subtype affinity profile [37].
A summary of the ideal characteristics of the biologic target for targeted cancer therapy is listed in Table 10.7.
10.2.2 Clinical Studies
As mentioned earlier, the treatment-challenging properties of high-grade brain tumours and the failure of an across-the-board treatment to improve overall survival (OS) indicate an urgent need to develop an effective therapeutic. In this regard, precision medicine can provide a tailored treatment based on the individual biologic targets expressed by the tumours. PRRT is an initiative approach to more accurately treat these tumours.
The first PRRT study was conducted by Merlo et al. [38]. They treated 11 patients (seven low-grade and four anaplastic glioma patients) by locoregional administration of 111In-DOTA0D- Phe1Tyr3]-octreotide (111In-DOTATOC) and 90Y-labeled DOTATOC. In this proof-of-concept study, patients were treated with intra-tumoral injection of radioconjugate via a port-a-cath-like device. Furthermore, they showed a homogeneous distribution and stable peptide-to-receptor binding of 111In-DOTATOC on the tumour cells surface. The administered dose was one-to-four fractions based on the tumour volume; 1110MBq of 90Y-labeled DOTATOC was the maximum dose per each injection. Six stable diseases and the shrinking of a cystic low-grade astrocytoma tumour were achieved. The toxicity profile included secondary perifocal oedema. The authors claimed that the activity/dose ratio (MBq/Gy) may serve as a potential prognostic factor for the clinical course of the disease.
Recently, we assessed the treatment efficacy of intravenous 177Lu-DOTATATE in patients with high-grade astrocytoma; the results were promising (Fig. 10.1).
Peptide receptor radionuclide therapy for 63-year-old women with glioblastoma multiforme in left striatum. There is remarkable uptake in the tumour on post-therapy images using 177Lu-DOTATATE (3.7 GBq). The patient had received three cycles of 177Lu-DOTATATE and achieved a stable course since starting therapy. This figure also depicts the ubiquitous and homogeneous distribution of the radioconjugate throughout the tumour tissue following iv injection
However, further well-designed studies to determine absorbed dose; more precise protocols based on tumour invasiveness, aggressiveness, malignant transformation and histological classification; as well as long-term outcome and the effect of this therapeutic on laboratory parameters are highly warranted. A list of selected clinical studies is presented in Table 10.8.
10.3 Immune-Based Radionuclide Therapy
10.3.1 Biologic Targets for RIT
10.3.1.1 Tenascin-C
Tenascin-C (TN-C) is a hexa-brachion polymorphic glycoprotein of the extracellular matrix (ECM) expressed in both normal conditions and disorders. TN-C is expressed far and wide in pathologic conditions such as wound healing, inflammatory processes and tumorigenesis; it also has a short-term physiological expression during embryogenesis and organogenesis [42]. Regarding tumorigenesis, the key function of TN-C is to ease the migration of tumour cells from the ECM to other body parts [43]. Approximately 90% of glioma tumour cells show extensive expression of TN-C, particularly glioblastomas, contrary to normal cells which express it to a minor extent [42, 44, 45]. TN-C was shown to have immunoreactivity in the tumoral vessels and the tumour networks of high-grade astrocytoma tumours [46]. Furthermore, TN-C is expressed in the tumoral vessels in higher levels in high-grade compared to low-grade astrocytoma tumours [46]. TN-C expression is associated with proliferative rate, angiogenesis and progressive growing pattern [46]. Regarding the overexpression of TN-C in gliomas and its crucial role in tumour proliferation, migration, progression and angiogenesis, it seems that targeting TN-C can serve as a targeted therapy approach based on tumour biology in selected patients [46,47,48]. So far, several antibodies have been designed to target TN-C; these are classified as murine monoclonal antibodies (mmAbs) and chimeric antibodies (cAbs). mmAbs against TN-C include BC-2, BC-4, 81C6, ST2146, ST2485, F16 and P12; cAbs consist of ch81C6 [49,50,51]. These antibodies have been studied in the pre-clinical setting; if they show promise, they are eligible for translation into clinical trials [52, 53].
10.3.1.2 Epidermal Growth Factor Receptor
Epidermal growth factor receptor (EGFR) is a transmembrane protein that functions as a receptor for a protein ligand belonging to the epidermal growth factor family [54]. The binding of the ligand to the EGFR causes the phosphorylation of receptor tyrosine kinase and activates downstream signal transduction pathways involved in cellular proliferation rate regulation, differentiation and survival [54]. Moreover, EGFR overexpression is associated with some cancers such as brain neoplasms [55]. It has been detected in about 57% of GBM tumours [55]. EGFR has an important role in tumour cell proliferation and survival; therefore, EGFR blockage can interrupt intracellular signalling. Thus, it has gained meaningful attention as a biological target for RIT in brain tumours. Thus far, two types of therapeutics have been made to inhibit EGFR activity: mAbs that target EGFR and tyrosine kinase inhibitors (TKIs) that prohibit EGFR-related signalling pathways. These mAbs include nimotuzumab, cetuximab and monoclonal antibody-425, while the TKIs consist of erlotinib and gefitinib. Both of these drug types have been investigated in preclinical and clinical trials [56,57,58,59,60,61,62,63,64,65].
10.3.1.3 Neural Cell Adhesion Molecule
Neural cell adhesion molecule (NCAM) is a glycoprotein on the cell surface that has Ig-like and fibronectin type III (FnIII) domains in its structure and is classified in the immunoglobulin (Ig) superfamily. Within the central nervous system (CNS), these molecules contribute to cell group formation, NCAM-related neurite outgrowth and synaptic plasticity [66, 67]. Because NCAM has been found ubiquitously in some cancers such as brain neoplasms, NCAM-targeted therapy for these tumours has received significant attention. Several mAbs have been created against NCAM including 131I-UJ13A, 131I-ERIC-1 and 90Y-ERIC1; they have been tested in pre-clinical and clinical studies of RIT for brain neoplasms [68,69,70,71].
10.3.1.4 Histone H1
Tumour necrosis therapy (TNT) is an innovative strategy in the targeted therapy of cancers; it uses mAbs or fragments of such to aim at an intracellular antigen of the necrotic debris of the tumour [72]. Tumours of the brain contain areas of necrosis in which the cells have higher cell membrane permeability; thus, several immunoglobulins are able to enter the cells [72]. Furthermore, histone H1 is a linker histone; it is found in the nucleus and is involved with nucleosomal arrays for increased compacting of the nucleosomes in order to form a higher-level chromatin structure [73]. There is a widespread expression of the molecule in the necrotic areas of brain tumours. Therefore, it can be targeted using a mAb equipped with a radionuclide payload [72]. ChTNT-1/B mAb is a genetically engineered chimeric mAb capable of specifically binding to the DNA-bound histone H1 in order to form an insoluble and non-diffusible anchor for the bounded mAb [72]. Recently, it has been attached to 131I and has been applied in the treatment of GBM tumours [72, 74].
10.3.2 Future Novel Targets
10.3.2.1 Fibulin-3
Fibulin-3 is a glycoprotein of the extracellular matrix (ECM) typically detected in healthy connective tissues. The molecule is absent in normal brain tissue; however, it is expressed by GBM cells and is found in the ECM of tumour tissue [75,76,77]. Moreover, fibulin-3 can initiate Notch and NF-κB signalling pathways by autocrine and paracrine paths that have not been described in healthy tissues [75, 77, 78]. Fibulin-3 intensifies the capacity for invasion, neovascularization and survival in the tumour-initiating cell population of GBM; it is related with poor prognosis and represents a biomarker of active progression [79, 80]. Hence, the pivotal role of fibulin-3 in the biology of GBM and the significant tumour-to-background ratio potentially make it an appealing molecular target for cancer therapy. Nandhu et al. introduced a function-inhibitor antibody that targets fibulin-3, named mAb428.2, that was designed to treat GBM tumours in a mouse model [81]. They treated mice carrying xenograft subcutaneous or intracranial GBM by administration of mAb428.2 via either iv or intra-tumoral injection. The results show promise; mAb428.2 successfully bound to the target and inhibited the fibulin-3 from starting ADAM17, Notch and NF-κB signalling in the cells of GBM and finally reduced tumour growth, invasion and neovascularization, and improved the survival of the mice.
Another study reported that anti-fibulin-3-targeted therapy for GBM can strengthen anti-tumour inflammatory response [82]. Taking the available evidence together, fibulin-3 represents a promising biological target for the treatment of these tumours, particularly for RIT where it is joined with a radionuclide payload. Also, fibulin-3-based RIT may provide promising therapeutics due to a high tumour-to-background ratio that enables it to reach the tumour tissue while minimizing damage to the nearby non-tumoral tissues.
10.3.3 Clinical Studies
The clinical studies of the application of RIT in brain tumours are summarized in Tables 10.9 and 10.10.
10.3.4 Challenges and Future Directions
10.3.4.1 Challenges
Brain tumours present as aggressive tumours with very poor prognosis despite optimal available treatment. Of those several reasons for therapeutic failure mentioned above, two represent the crucial parameters contributing to clinical trial failure; thus, should be considered as among important factors for treatment planning. The first is the physical barricading function of the BBB and the latter is inter- and intra-tumoral heterogeneity.
10.3.4.2 The Blood-Brain Barrier (BBB)
Given the biologic properties of the intact BBB, many drugs are prohibited from passing through it to reach the brain parenchyma; an interrupted BBB allows the selective passage of larger substances (antibodies or larger peptides). However, all the parts of brain tumours are not covered by the interrupted BBB and some parts are not accessible due to shielding behind an intact BBB.
The locoregional administration of therapeutics (chemotherapeutic or radiolabelled payloads) is designed to circumvent this obstacle in the treatment strategy. However, this method has faced some challenging issues including significant local toxicity profile, lack of anti-tumour efficacy (pharmacodynamic failure) and local complications such as radioconjugate leaking, local pain, local bleeding and local infection/inflammation.
Another approach is the application of drugs that are small enough to pass through the intact BBB. However, an effective drug of sufficiently small molecular size has yet to be developed.
Before the introduction of tumour-selective therapeutics, cancers were treated by nonspecific cytotoxic drugs that harm many parts in the body with early/late and transient/permanent complications. Given the low therapeutic effect, high cytotoxic profile of the drugs and their significant side effects, survival remained impoverished. Therefore, the precision medicine concept aimed to introduce targeted therapy to selectively target tumour cells while minimizing damage to other parts of the body. Notable progress has been made, but several challenges still remain.
10.3.4.3 Tumoral Heterogeneity
Another important factor in treatment failure is tumour heterogeneity. Tumour heterogeneity may be classified as inter- and intra-tumoral heterogeneity depending upon the different genetic characteristics and molecular profile not only between patients but also within each subject. It is well-known that high-grade brain tumours are composed of multiple tumour cell colonies with different genetic properties and molecular profiles. Interestingly, the precision medicine concept, which involves giving the right drug to the right patient, can provide a personalized solution to circumvent inter- and intra-tumoral heterogeneity.
There is an unmet need in regard to the lack of classification of patients in clinical trials based on the molecular and genetic profile of their tumours; the intertumoral heterogeneity in brain tumours usually results in an inhomogeneous patient group that shows variable therapeutic responses to the same treatment. Therefore, these heterogeneities necessitate the sorting of patients with high-grade tumours according to genetic characteristics, molecular profile and constitutional tumoral cell colonies. This approach can optimize the precision medicine concept to circumvent inter-tumoral heterogeneity by aiming to deliver the right drug to the right patients in order to provide the optimal therapeutic benefits (Fig. 10.2).
Precision medicine approach in brain tumours
So far, few clinical trials have incorporated molecular and genetic properties into their study design and patients are simply divided into a new case group and a recurrent disease group. However, these patient groups are highly inhomogeneous due to vast tumoral heterogeneity and overly simple classification strategies. Moreover, an assessment of treatment efficacy in an inhomogeneous patient group will probably lead to inconclusive results and misinterpretation of the true therapeutic benefits, and may mask the responding patient population.
Regardless of the many possible reasons for the failure of a clinical trial, inhomogeneous patient population and intertumoral heterogeneity are major issues that challenge the merits of an effective clinical trial and have yet to be addressed. This obstacle can be tackled by incorporating individual biologic data into patient classification, such as molecular profile, genetic characteristics and the immunologic properties of the tumour cell colonies.
Unfortunately, the molecular, genetic and immunologic characteristics of high-grade glioma tumours have not been fully discovered to date. Therefore, an alternative strategy is to identify and separate patients who respond to a given drug in a routine clinical trial, and to explore the biologic properties contributing to the therapeutic response. This alternative strategy can grant us a better insight into the biologic principles of tumorigenesis and help to identify biomarkers for patient classification and disease prognostication.
Following biology-based classification of the patients, another issue that needs to be addressed is that of intratumoral heterogeneity, which can be eluded by targeting multiple biologic targets in order to target all of the constitutional tumoral colonies. The best solution is the coupling of a radionuclide payload and an mAb with an intrinsic tumoricidal property that allows us to fight cancer cells more efficiently.
10.3.5 Conclusion
Early and effective intervention is mandatory in the early stages of high-grade gliomas due to the extensive and irreversible destruction of healthy neural tissues by the tumour. It is time to reconsider recommending an across-the board treatment without patient classification based on individual biologic profile. Biology-based patient classification and individual-based multiple-targeted therapy are essential prerequisites of a tailored personalized management that would pave the way toward an effective treatment for brain tumours.
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Assadi, M., Nemati, R., Shooli, H., Ahmadzadehfar, H. (2024). Radionuclide Therapy in Brain Tumours. In: Prasad, V. (eds) Beyond Becquerel and Biology to Precision Radiomolecular Oncology: Festschrift in Honor of Richard P. Baum. Springer, Cham. https://doi.org/10.1007/978-3-031-33533-4_10
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